Compounds and compositions for treating conditions associated with APJ receptor activity

ABSTRACT

This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt and/or hydrate and/or prodrug of the compound) that modulate (e.g., agonize) the apelin receptor (also referred to herein as the APJ receptor, gene symbol APLNR). This disclosure also features compositions containing the same as well as other methods of using and making the same. The chemical entities are useful, e.g., for treating a subject (e.g., a human) having a disease, disorder, or condition in which a decrease in APJ receptor activity (e.g., repressed or impaired APJ receptor signaling; e.g., repressed or impaired apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathology and/or symptoms and/or progression of the disease, disorder, or condition. Non-limiting examples of such diseases, disorders, or conditions include: (i) cardiovascular disease; (ii) metabolic disorders; (iii) diseases, disorders, and conditions associated with vascular pathology; and (iv) organ failure; (v) diseases, disorders, and conditions associated with infections (e.g., microbial infections); and (vi) diseases, disorders, or conditions that are sequela or comorbid with any of the foregoing or any disclosed herein. More particular non-limiting examples of such diseases, disorders, or conditions include pulmonary hypertension (e.g., PAH); heart failure; type II diabetes; renal failure; sepsis; and systemic hypertension.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.17/282,619, filed on Apr. 2, 2021, which is a National Stage applicationunder 35 U.S.C. § 371 of International Patent Application No.PCT/US2019/054880, filed on Oct. 4, 2019, which claims the benefit ofU.S. Provisional Application No. 62/742,218, filed on Oct. 5, 2018,which are incorporated herein by reference in their entirety.

TECHNICAL FIELD

This disclosure features chemical entities (e.g., a compound or apharmaceutically acceptable salt and/or hydrate and/or prodrug of thecompound) that modulate (e.g., agonize) the apelin receptor (alsoreferred to herein as the APJ receptor; gene symbol “APLNR”). Thisdisclosure also features compositions containing the same as well asother methods of using and making the same. The chemical entities areuseful, e.g., for treating a subject (e.g., a human) having a disease,disorder, or condition in which a decrease in APJ receptor activity(e.g., repressed or impaired APJ receptor signaling; e.g., repressed orimpaired apelin-APJ receptor signaling) or downregulation of endogenousapelin contributes to the pathology and/or symptoms and/or progressionof the disease, disorder, or condition. Non-limiting examples of suchdiseases, disorders, or conditions include: (i) cardiovascular disease;(ii) metabolic disorders; (iii) diseases, disorders, and conditionsassociated with vascular pathology; and (iv) organ failure; (v)diseases, disorders, and conditions associated with infections (e.g.,microbial infections); and (vi) diseases, disorders, or conditions thatare sequela or comorbid with any of the foregoing or any disclosedherein. More particular non-limiting examples of such diseases,disorders, or conditions include pulmonary hypertension (e.g., PAH);heart failure; type II diabetes; renal failure; sepsis; and systemichypertension.

BACKGROUND

Pulmonary arterial hypertension (PAH) is a severe cardiopulmonarydisorder characterized by the vascular remodeling of the pulmonaryarterioles, including formation of plexiform and concentric lesionscomprised of proliferative vascular cells. PAH is believed to be causedby cellular proliferation and fibrosis of the small pulmonary arteries.Clinically, PAH leads to increased pulmonary arterial pressure andsubsequent right ventricular failure, which is one of the major causesof morbidity and mortality. Mortality rates remain exceedingly high with15%, 30%, and 45% mortality at 1, 2, and 3 years after diagnosis,respectively. See, e.g., Kim, J., Mol. Cells 2014; 37(3): 196-201 andLau, E. M. T., Nature Reviews, 2017, 1-12.

Diabetes mellitus type 2 (type-2 diabetes) is characterized by highblood glucose and insulin resistance. Type 2 diabetes as well asconditions that are co-morbid or sequela with type-2 diabetes affecttens of millions of people in the United States alone. Type-2 diabetesis frequently associated with obesity.

The apelin or APJ receptor is a G protein-coupled receptor containingseven hydrophobic transmembrane domains (see, e.g., Kim, supra). Apelin(also known as APLN) is a 36 amino acid peptide that in humans isencoded by the APLN gene and is the endogenous ligand for the APJreceptor (see, e.g., O'Carroll, A-M., et al., J Endocrinol 2013, 219,R13-R35).

The apelin/APJ system is present in many tissues such as heart, kidney,pancreas, lung, vasculature, central nervous system, liver, adipose,gastrointestinal tract, brain, adrenal glands, endothelium, and humanplasma.

Additionally, there is evidence showing that both apelin and APJ areregulators of central and peripheral responses to multiple homeostaticperturbations such as cardiovascular control and function; angiogenesis;fluid homeostasis; water balance; hypothalamic-pituitary-adrenal (HPA)axis regulation; metabolic homeostasis; energy metabolism; and kidneyfunction. For example, there is emerging evidence that APJ-apelinsignaling plays a role in the maintenance of pulmonary vascularhomeostasis (see, e.g., Kim supra). Evidence also points to a nexusbetween apelinergic system (e.g., apelin and APJ receptor) and thetreatment of conditions such as sepsis, septic shock, and renal failure(see, e.g., Coquerel, D., et al., Critical Care 2018, 22: 10). Asanother example, apelin, synthesized and secreted by adipocytes, hasbeen described as a beneficial adipokine related to obesity, and thereis additional evidence of a potential role for apelin and APJ receptorin glucose and energy metabolism (see e.g., O'Carroll supra).

SUMMARY

This disclosure features chemical entities (e.g., a compound or apharmaceutically acceptable salt and/or hydrate and/or prodrug of thecompound) that modulate (e.g., agonize) the apelin receptor (alsoreferred to herein as the APJ receptor; gene symbol “APLNR”). Thisdisclosure also features compositions containing the same as well asother methods of using and making the same. The chemical entities areuseful, e.g., for treating a subject (e.g., a human) having a disease,disorder, or condition in which a decrease in APJ receptor activity(e.g., repressed or impaired APJ receptor signaling; e.g., repressed orimpaired apelin-APJ receptor signaling) or downregulation of endogenousapelin contributes to the pathology and/or symptoms and/or progressionof the disease, disorder, or condition. Non-limiting examples of suchdiseases, disorders, or conditions include: (i) cardiovascular disease;(ii) metabolic disorders; (iii) diseases, disorders, and conditionsassociated with vascular pathology; and (iv) organ failure; (v)diseases, disorders, and conditions associated with infections (e.g.,microbial infections); and (vi) diseases, disorders, or conditions thatare sequela or comorbid with any of the foregoing or any disclosedherein. More particular non-limiting examples of such diseases,disorders, or conditions include pulmonary hypertension (e.g., PAH);heart failure; type 11 diabetes; renal failure; sepsis; systemichypertension; idiopathic pulmonary fibrosis (IPF); and systemicsclerosis.

An “agonist” of the APJ receptor includes compounds that, at the proteinlevel, directly bind or modify the APJ receptor such that an activity ofthe APJ receptor is increased, e.g., by activation, stabilization,altered distribution, or otherwise.

Certain chemical entities described herein that agonize the APJ receptorto a lesser extent than an APJ receptor full agonist can function inassays as antagonists as well as agonists. These chemical entitiesantagonize activation of the APJ receptor by an APJ receptor fullagonist because they prevent the full effect of APJ receptorinteraction. However, the chemical entities also, on their own, activatesome APJ receptor activity, typically less than a corresponding amountof the APJ receptor full agonist. Such chemical entities are sometimesreferred to herein as “partial agonists of the APJ receptor”.

In some embodiments, the chemical entities described herein are agonists(e.g. full agonists) of the APJ receptor. In other embodiments, thechemical entities described herein are partial agonists of the APJreceptor.

In other embodiments, the chemical entities described herein modulate(e.g., agonize) the APJ receptor in a pathway-specific manner.Accordingly, this disclosure also features chemical entities thatexhibit activity as ligand-biased modulators (e.g., ligand-biasedagonists). APJ receptor activity can modulate (e.g., alter or bias)competing levels of downstream G-protein signaling (activation) andβ-arrestin recruitment. APJ receptor signaling through β-arrestin hasbeen shown to mediate stretch-induced myocardial hypertrophy. See, e.g.,Scimia, M. C., et al., Nature 2012, 488, 394-398. In certainembodiments, the chemical entities described herein modulate (e.g.,reduce, e.g., attenuate, disrupt, inhibit) β-arrestin signaling. Incertain embodiments, the chemical entities described herein modulate(e.g., reduce, e.g., attenuate, disrupt, inhibit) recruitment ofβ-arrestin.

In certain embodiments, the chemical entities described herein activateor increase the levels of downstream G-protein signaling.

In certain embodiments, the chemical entities described herein inhibitor decrease the levels of β-arrestin recruitment.

In certain embodiments, the chemical entities described herein activateor increase the levels of β-arrestin recruitment.

In certain embodiments, the chemical entities described hereinselectively modulate (e.g., increase) one of the pathways over theother. For example, the chemical entities described herein can activateor increase the levels of downstream G-protein signaling, and inhibit ordecrease the levels of β-arrestin recruitment.

In other embodiments, the chemical entities described herein canactivate or increase the levels of downstream G-protein signaling, andactivate or increase the levels of β-arrestin recruitment. For example,the chemical entities described herein can fully agonize both β-arrestinand G protein signaling pathways.

Generally, a receptor exists in an active (Ra) and an inactive (Ri)conformation. Certain compounds that affect the receptor can alter theratio of Ra to Ri (Ra/Ri). For example, a full agonist increases theratio of Ra/Ri and can cause a “maximal”, saturating effect. A partialagonist, when bound to the receptor, gives a response that is lower thanthat elicited by a full agonist (e.g., an endogenous agonist). Thus, theRa/Ri for a partial agonist is less than for a full agonist. However,the potency of a partial agonist may be greater or less than that of thefull agonist.

In one aspect, the featured chemical entities include compounds ofFormula I, or a pharmaceutically acceptable salt thereof:

in which R¹, R², A¹, X¹, X², X³, and X⁴ can be as defined anywhereherein.

In one aspect, pharmaceutical compositions are featured that include achemical entity described herein (e.g., a compound described genericallyor specifically herein or a pharmaceutically acceptable salt thereof orcompositions containing the same) and one or more pharmaceuticallyacceptable excipients.

In one aspect, methods for modulating (e.g., agonizing, partiallyagonizing,) APJ receptor activity are featured that include contactingthe APJ receptor with a chemical entity described herein (e.g., acompound described generically or specifically herein or apharmaceutically acceptable salt thereof or compositions containing thesame). Methods include in vitro methods, e.g., contacting a sample thatincludes one or more cells, each independently comprising one or moreAPJ receptors with the chemical entity. Methods can also include in vivomethods. Such methods can include, e.g., administering the chemicalentity to a subject (e.g., a human) having a disease, disorder, orcondition in which a decrease in APJ receptor activity (e.g., repressedor impaired APJ receptor signaling; e.g., repressed or impairedapelin-APJ receptor signaling) or downregulation of endogenous apelincontributes to the pathology and/or symptoms and/or progression of thedisease, disorder, or condition (e.g., PAH; heart failure; type IIdiabetes; sepsis; renal failure; and systemic hypertension). In vivomethods include, but are not limited to modulating (e.g., decreasing)right ventricular afterload; modulating (e.g., decreasing) meanpulmonary artery pressure; modulating (e.g., increasing) insulin levels;and modulating (e.g., decreasing) glucose levels in a subject (e.g., ahuman).

In a further aspect, methods of treatment of a disease, disorder, orcondition are featured, in a decrease in APJ receptor activity (e.g.,repressed or impaired APJ receptor signaling; e.g., repressed orimpaired apelin-APJ receptor signaling) or downregulation of endogenousapelin contributes to the pathology and/or symptoms and/or progressionof the disease, disorder, or condition. The methods includeadministering to a subject in need of such treatment an effective amountof a chemical entity described herein (e.g., a compound describedgenerically or specifically herein, a pharmaceutically acceptable saltthereof, or compositions containing the same).

In another aspect, this disclosure features methods of treating asubject having a disease, disorder, or condition in which a decrease inAPJ receptor activity (e.g., repressed or impaired APJ receptorsignaling; e.g., repressed or impaired apelin-APJ receptor signaling) ordownregulation of endogenous apelin contributes to the pathology and/orsymptoms and/or progression of the disease, disorder, or condition. Themethods include administering a chemical entity described herein (e.g.,a compound described generically or specifically herein, apharmaceutically acceptable salt thereof or compositions containing thesame) in an amount effective to treat the disease, disorder, orcondition.

In a further aspect, methods of treatment are featured that includeadministering to a subject chemical entity described herein (e.g., acompound described generically or specifically herein, apharmaceutically acceptable salt thereof, or compositions containing thesame). The methods include administering the chemical entity in anamount effective to treat a disease, disorder, or condition, wherein adecrease in APJ receptor activity (e.g., repressed or impaired APJreceptor signaling; e.g., repressed or impaired apelin-APJ receptorsignaling) or downregulation of endogenous apelin contributes to thepathology and/or symptoms and/or progression of the disease, disorder,or condition, thereby treating the disease, disorder, or condition.

A non-limiting example of such diseases, disorders, and conditions isPAH. In some embodiments, the PAH is idiopathic. In other embodiments,the PAH is heritable PAH, toxin or drug-induced PAH; or a PAH associatedwith one or more of the following: congenital heart disease, connectivetissue disorders (e.g., scleroderma, systemic lupus erythematosus,systemic sclerosis, Hashimoto's thyroiditis, Sjogren's Syndrome, and theantiphospholipid antibody syndrome), portal hypertension, BMPR2mutations, Schistosomiasis, and HIV infection.

Another non-limiting example of such diseases, disorders, and conditionsis cardiovascular disease, e.g., coronary heart disease and heartfailure. In certain embodiments, the cardiovascular disease is heartfailure; e.g., systolic heart failure, diastolic heart failure, diabeticheart failure and heart failure with preserved ejection fraction,cardiomyopathy, myocardial infarction, left ventricular dysfunctionincluding left ventricular dysfunction after myocardial infarction,right ventricular dysfunction, right ventricular failure, cardiachypertrophy, myocardial remodeling including myocardial remodeling afterinfarction or after cardiac surgery, and valvular heart diseases.

Still another non-limiting example of such diseases, disorders, andconditions is a metabolic disorder, such as metabolic syndrome; diabetes(e.g., type 2 diabetes); obesity; obesity-related disorders; impairedglucose tolerance; and insulin resistance.

Other non-limiting examples of such diseases, disorders, and conditionsinclude sepsis, septic shock, renal failure, systemic hypertension,idiopathic pulmonary fibrosis (IPF), and systemtic sclerosis.

Further non-limiting examples include coronary artery disease (CAD),non-CAD atherosclerotic conditions, including peripheral vasculardisease (PVD), aortic atherosclerosis, and cerebral arteriosclerosis,diabetic retinopathy, ischemia-reperfusion injury, emphysema,radiation-induced organ and tissue injury, corpus luteum regression,scleroderma, systemic sclerosis, and diseases of immune dysregulation.

In one aspect, this disclosure features methods for identifying and/orselecting a subject (e.g., a human) likely to benefit from the methodsdescribed herein, as well as methods for determining whether a subject(e.g., a human) is responding to such methods. In certain embodiments, abiological sample, which may be, for example and without limitation, abreath, sputum, tissue, plasma or serum sample, urine, is obtained fromthe subject, and the level of a particular parameter in the sample isdetermined and compared to a control value. In some instances, thecontrol value may be determined from one or more normal individuals notsuffering from the disease, disorder, or conditions being treated. Inother instances, the control value can also be determined from a samplepreviously obtained from the subject. Generally, higher (or elevated)levels of the measured parameter relative to a control value determinedfrom a normal, non-diseased individual or population indicate that asubject will benefit from methods described herein. Lower levelsgenerally indicate that a patient is responding to therapy or, for asubject not on such therapy, that the therapeutic methods may not be asbeneficial for that subject.

In certain of the foregoing embodiments, the subject is suffering from,or at risk of suffering from PAN. Non-limiting, exemplary parametersrelated to PAH are delineated below.

In certain embodiments, the parameter is LTB4 level. For example, abaseline or reference value of LTB4 can be 100 pg/mL or greater, 200pg/mL or greater, 300 pg/mL or greater, 400 pg/mL or greater, 500 pg/mLor greater, 600 pg/mL or greater, or 100 pg/mL or greater. In certainembodiments, the treatment provided is efficacious if, after treatmenthas started, the endpoint LTB4 level of the subject decreases from thebaseline or reference LTB4 level. For example, the endpoint LTB4 levelof the subject decreases to 600 pg/mL or less, 500 pg/mL or less, 400pg/mL or less, 300 pg/mL or less, 200 pg/mL or less, or 100 pg/mL orless. In certain embodiments, the treatment provided is efficacious if,after treatment has started, the endpoint LTB4 level is 30 pg/mg oftissue or lower, 20 pg/mg of tissue of lower, 10 pg/mg of tissue orlower, 7.5 pg/mg of tissue or lower, or 5 pg/mg of tissue or lower. Inother embodiments, the treatment provided is efficacious if, aftertreatment has started, the endpoint LTB4 level is lower than thebaseline LTB4 level by 2-fold or more, 3-fold or more, 4-fold or more,or 5-fold or more.

In certain embodiments, the parameter is pulmonary vascular resistance(PVR). The baseline or reference PVR level can be 200 dynsec/cm⁵ orgreater, 240 dynsec/cm⁵ or greater, 300 dynsec/cm⁵ or greater, 400dynsec/cm⁵ or greater, 500 dynsec/cm⁵ or greater, 600 dynsec/cm⁵ orgreater, 700 dynsec/cm⁵ or greater, or 800 dynsec/cm⁵ or greater. Incertain embodiments, the treatment provided is efficacious if, aftertreatment has started, the endpoint PVR level of the subject decreasesfrom the baseline or reference PVR level by 70 dynsec/cm⁵ or more, 100dynsec/cm⁵ or more, 130 dynsec/cm⁵ or more, or 160 dynsec/cm⁵ or more.

In certain embodiments, the parameter is pulmonary arterial pressure(PAP). The baseline or reference PAP level can be 20 mmHg or greater, 25mmHg or greater, 30 mmHg or greater, 35 mmHg or greater, 40 mmHg orgreater, 45 mmHg or greater, 50 mmHg or greater, 60 mmHg or greater, or70 mmHg or greater. In certain embodiments, the treatment provided isefficacious if, after treatment has started, the endpoint PAP level ofthe subject decreases from the baseline or reference PAP level by 0.5mmHg or more, 1 mmHg or more, 1.5 mmHg or more, 5 mmHg or more, 10 mmHgor more, 20 mmHg or more, 30 mmHg or more, 40 mmHg or more, or 50 mmHg.In certain embodiments, the subject exhibits a mean pulmonary arterypressure of greater than 25 mmHg.

In certain embodiments, the parameter is cardiac index (CI). A baselineor reference CI level can be 5 L/min/m.sup.2 or lower, 2.5 L/min/m.sup.2or lower, 2 L/min/m.sup.2 or lower, 1.5 L/min/m.sup.2 or lower, or 1L/min/m.sup.2 or lower. In certain embodiments, the treatment providedis efficacious if, after treatment has started, the endpoint CI levelincreases from the baseline or reference CI level by 0.1 or more, 0.2 ormore, 0.3 or more, 0.4 or more, 0.5 or more, 1 or more, or 2 or more.

In certain embodiments, the parameter is pulmonary capillary wedgepressure (PCWP). A baseline or reference PCWP level can be 36 mmHg orless, 24 mmHg or less, 18 mmHg or less, 10 mmHg, or 5 mmHg or less. Incertain embodiments, the treatment provided is efficacious if, aftertreatment has started, the endpoint PCWP level increases from thebaseline or reference PCWP level by 0.2 mmHg or more, 0.3 mmHg or more,0.4 mmHg or more, 0.5 mmHg or more, 0.6 mmHg or more, 1 mmHg or more, or5 mmHg or more.

In certain embodiments, the parameter is right atrial pressure (RAP). Abaseline or reference RAP level can be 4 mmHg or more, 6 mmHg or more, 8mmHg or more, 10 mmHg or more, 12 mmHg or more, 16 mmHg or more, 20 mmHgor more, or 25 mmHg or more. In certain embodiments, the treatmentprovided is efficacious if, after treatment has started, the endpointRAP level of the subject decreases from the baseline or reference RAPlevel by 5 mmHg or more 2.5 mmHg or more, 1 mmHg or more, 0.5 mmHg ormore, or 0.2 mmHg or more.

In certain embodiments, the parameter is the six-minute walk distance (6MWD). A baseline or reference 6 MWD can be 50 m or less, 100 m or less,200 m or less, 300 m or less, 400 m or less, or 500 m or less. Incertain embodiments, the treatment provided is efficacious it aftertreatment has started, the endpoint 6 MWD of the subject increases fromthe baseline or reference 6 MWD by 10 m or more, 15 m or more, 20 m ormore, 25 m or more, 30 m or more, or 50 m or more. Alternatively or inaddition, treatment provided in the invention is efficacious if, aftertreatment has started, the endpoint 6 MWD of the subject increases by 3%or more, 4% or more, 5% or more, 10% or more, or 20% or more of thebaseline level.

In certain embodiments, the parameter is brain natriuretic peptide (BNP)level. A baseline or reference BNP level can be 60 pg/mL or higher, 80pg/mL or higher, 100 pg/mL or higher, 120 pg/mL or higher, 140 pg/mL orhigher, 200 pg/mL or higher, 500 pg/mL or higher, or 1000 pg/mL orhigher. In certain embodiments, the treatment provided is efficaciousif, after treatment has started, the endpoint BNP level of the subjectdecreases from the baseline or reference BNP level. For example, theendpoint BNP level of the subject can decrease by 1 pg/mL or more, 2pg/mL or more, 5 pg/mL or more, 10 pg/mL or more, 20 pg/mL or more, 100pg/mL or more, 500 pg/mL or more, or 1000 pg/mL or more.

In certain embodiments, the parameter is atrial natriuretic peptide(ANP) level. A baseline or reference ANP level can be 60 pg/mL orhigher, 80 pg/mL or higher, 100 pg/mL or higher, 120 pg/mL or higher,140 pg/mL or higher, 200 pg/mL or higher, 500 pg/mL or higher, or 1000pg/mL or higher. In certain embodiments, the treatment provided isefficacious if, after treatment has started, the endpoint ANP level ofthe subject decreases from the baseline or reference ANP level. Forexample, the endpoint ANP level of the subject can decrease by 1 pg/mLor more, 2 pg/mL or more, 5 pg/mL or more, 10 pg/mL or more, 20 pg/mL ormore, 100 pg/mL or more, 500 pg/mL or more, or 1000 pg/mL or more.

In certain embodiments, the parameter is Diffusion of lung capacity(DLCO), or diffusion capacity of CO, can also be used in the methods asa parameter to determine efficacy. A baseline or reference DLCO can be90% or less, 80% or less, 70% or less, 50% or less, 45% or less, or 40%or less. In certain embodiments, the treatment provided is efficaciousif, after treatment has started, the endpoint DLCO is increased from thebaseline level. For example, the endpoint DLCO can be increased from thebaseline or reference DLCO by 1% or more, 5% or more, 10% or more, 15%or more, 20% or more, or 50% or more.

In another aspect, this disclosure features methods for reducing therisk of right ventricular failure in a subject in need of such reducing,the method comprising administering to the subject an effective amountof a chemical entity described herein.

The methods described herein can further include treating one or moreconditions that are associated, co-morbid or sequela with any one ormore of the conditions described herein.

For example, the methods can further include treating one or moreconditions that are associated, co-morbid or sequela with PAH, e.g.,coronary heart disease or heart failure. In certain embodiments, thecardiovascular disease is heart failure, e.g., systolic heart failure,diastolic heart failure, diabetic heart failure and heart failure withpreserved ejection fraction, cardiomyopathy, myocardial infarction, leftventricular dysfunction including left ventricular dysfunction aftermyocardial infarction, right ventricular dysfunction, right ventricularfailure, cardiac hypertrophy, myocardial remodeling including myocardialremodeling after infarction or after cardiac surgery, and valvular heartdiseases.

As another example, the methods can further include treating one or moreconditions that are co-morbid or sequela with diabetes (e.g., type 2diabetes), such as obesity, obesity-related disorders, metabolicsyndrome, impaired glucose tolerance; insulin resistance; cardiovascularrisk factors. (e.g., coronary artery disease, peripheral artery disease,cerebrovascular disease, hypertension, and risk factors related tounmanaged cholesterol and/or lipid levels, and/or inflammation),retinopathy, nephropathy, neuropathy, NASH, bone fracture and cognitivedysfunction.

The methods can further include administering one or more othertherapeutic agents (e.g., in combination with a chemical entitydescribed herein).

Embodiments can include one of more of the following advantageousproperties.

Apelin peptide is labile; as such, only acute pharmacodynamics effect ofapelin peptide is observable. In some embodiments, the compoundsdescribed herein exhibit relatively high metabolic stability to allowobservations of non-acute pharmacodynamics effect.

In some embodiments, the compounds described herein can lead to reducedatrial pressure in addition to enhancing cardiac output.

In some embodiments, the compounds described herein can selectivelyactivate the G-protein pathway through APJ receptor, thereby reducingtachyphylaxis often associated with dosing potent agonists. As such, incertain embodiments, compounds described herein can reducearrestin-associated cardiac hyperthrophy.

In some embodiments, the compounds described herein can exhibitpleiotropic properties (e.g., inodilator activity, cardio-renalprotection, and control of fluid homeostasis).

Other embodiments include those described in the Detailed Descriptionand/or in the claims.

Additional Definitions

To facilitate understanding of the disclosure set forth herein, a numberof additional terms are defined below. Generally, the nomenclature usedherein and the laboratory procedures in organic chemistry, medicinalchemistry, and pharmacology described herein are those well-known andcommonly employed in the art. Unless defined otherwise, all technicaland scientific terms used herein generally have the same meaning ascommonly understood by one of ordinary skill in the art to which thisdisclosure belongs. Each of the patents, applications, publishedapplications, and other publications that are mentioned throughout thespecification and the attached appendices are incorporated herein byreference in their entireties.

As used herein, the term “APJ receptor” is meant to include, withoutlimitation, nucleic acids, polynucleotides, oligonucleotides, sense andantisense polynucleotide strands, complementary sequences, peptides,polypeptides, proteins, homologous and/or orthologous APJ or APJreceptor molecules, isoforms, precursors, mutants, variants,derivatives, splice variants, alleles, different species, and activefragments thereof.

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

“API” refers to an active pharmaceutical ingredient.

The term “IC50” or “EC50” refers an amount, concentration, or dosage ofa compound that is required for 50% inhibition or activation of amaximal response in an assay that measures such response.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of a chemical entity (e.g., acompound described generically or specifically herein, apharmaceutically acceptable salt thereof, or compositions containing thesame) being administered which will relieve to some extent one or moreof the symptoms of the disease or condition being treated. The resultincludes reduction and/or alleviation of the signs, symptoms, or causesof a disease, or any other desired alteration of a biological system.For example, an “effective amount” for therapeutic uses is the amount ofthe composition comprising a compound as disclosed herein required toprovide a clinically significant decrease in disease symptoms. Anappropriate “effective” amount in any individual case is determinedusing any suitable technique, such as a dose escalation study.

The term “excipient” or “pharmaceutically acceptable excipient” means apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, carrier, solvent, or encapsulatingmaterial. In one embodiment, each component is “pharmaceuticallyacceptable” in the sense of being compatible with the other ingredientsof a pharmaceutical formulation, and suitable for use in contact withthe tissue or organ of humans and animals without excessive toxicity,irritation, allergic response, immunogenicity, or other problems orcomplications, commensurate with a reasonable benefit/risk ratio. See,e.g., Remington: The Science and Practice of Pharmacy, 21st ed.;Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook ofPharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; ThePharmaceutical Press and the American Pharmaceutical Association: 2009;Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; GowerPublishing Company: 2007; Pharmaceutical Preformulation and Formulation,2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

The term “pharmaceutically acceptable salt” refers to a formulation of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In certain instances, pharmaceuticallyacceptable salts are obtained by reacting a compound described herein,with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid,nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like. In some instances,pharmaceutically acceptable salts are obtained by reacting a compoundhaving acidic group described herein with a base to form a salt such asan ammonium salt, an alkali metal salt, such as a sodium or a potassiumsalt, an alkaline earth metal salt, such as a calcium or a magnesiumsalt, a salt of organic bases such as dicyclohexylamine,N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts withamino acids such as arginine, lysine, and the like, or by other methodspreviously determined. The pharmacologically acceptable salt s notspecifically limited as far as it can be used in medicaments. Examplesof a salt that the compounds described hereinform with a base includethe following: salts thereof with inorganic bases such as sodium,potassium, magnesium, calcium, and aluminum; salts thereof with organicbases such as methylamine, ethylamine and ethanolamine; salts thereofwith basic amino acids such as lysine and ornithine; and ammonium salt.The salts may be acid addition salts, which are specifically exemplifiedby acid addition salts with the following: mineral acids such ashydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,nitric acid, and phosphoric acid:organic acids such as formic acid,acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid,fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid,citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic aminoacids such as aspartic acid and glutamic acid.

The term “pharmaceutical composition” refers to a mixture of a compounddescribed herein with other chemical components (referred tocollectively herein as “excipients”), such as carriers, stabilizers,diluents, dispersing agents, suspending agents, and/or thickeningagents. The pharmaceutical composition facilitates administration of thecompound to an organism. Multiple techniques of administering a compoundexist in the art including, but not limited to rectal, oral,intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topicaladministration.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat,rabbit, rat, or mouse. The terms “subject” and “patient” are usedinterchangeably herein in reference, for example, to a mammaliansubject, such as a human.

The terms “treat,” “treating,” and “treatment,” in the context oftreating a disease, disorder, or condition, are meant to includealleviating or abrogating a disorder, disease, or condition, or one ormore of the symptoms associated with the disorder, disease, orcondition; or to slowing the progression, spread or worsening of adisease, disorder or condition or of one or more symptoms thereof.

The term “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo(I).

The term “alkyl” refers to a hydrocarbon chain that may be a straightchain or branched chain, containing the indicated number of carbonatoms. For example, C₁₋₁₀ indicates that the group may have from 1 to 10(inclusive) carbon atoms in it. Non-limiting examples include methyl,ethyl, iso-propyl, tert-butyl, n-hexyl.

The term “haloalkyl” refers to an alkyl, in which one or more hydrogenatoms is/are replaced with an independently selected halo.

The term “alkoxy” refers to an —O-alkyl radical (e.g., —OCH₃).

The term “haloalkoxy” refers to an —O-haloalkyl radical (e.g., —OCH₃).

The term “alkylene” refers to a branched or unbranched divalent alkyl(e.g., —CH₂—).

The term “arylene” and the like refer to divalent forms of the ringsystem, here divalent aryl.

The term “alkenyl” refers to a hydrocarbon chain that may be a straightchain or branched chain having one or more carbon-carbon double bonds.The alkenyl moiety contains the indicated number of carbon atoms. Forexample, C₂₋₆ indicates that the group may have from 2 to 6 (inclusive)carbon atoms in it.

The term “alkynyl” refers to a hydrocarbon chain that may be a straightchain or branched chain having one or more carbon-carbon triple bonds.The alkynyl moiety contains the indicated number of carbon atoms. Forexample, C₂₋₆ indicates that the group may have from 2 to 6 (inclusive)carbon atoms in it.

The term “aryl” refers to a 6-carbon monocyclic, 10-carbon bicyclic, or14-carbon tricyclic aromatic ring system wherein 0, 1, 2, 3, or 4 atomsof each ring may be substituted by a substituent, and wherein the ringcomprising a monocyclic radical is aromatic and wherein at least one ofthe fused rings comprising a bicyclic or tricyclic radical is aromatice.g. tetrahydronaphthyl. Examples of aryl groups also include phenyl,naphthyl and the like.

The term “cycloalkyl” as used herein includes saturated cyclichydrocarbon groups having 3 to 10 carbons, preferably 3 to 8 carbons,and more preferably 3 to 6 carbons, wherein the cycloalkyl group may beoptionally substituted. Preferred cycloalkyl groups include, withoutlimitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

The term “heteroaryl” refers to an aromatic 5-8 membered monocyclic,8-12 membered bicyclic, or 11-14 membered tricyclic ring system having1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S(e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S ifmonocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, 3,or 4 atoms of each ring may be substituted by a substituent, and whereinthe ring comprising a monocyclic radical is aromatic and wherein atleast one of the fused rings comprising a bicyclic or tricyclic radicalis aromatic (but does not have to be a ring which contains a heteroatom,e.g. tetrahydroisoquinolinyl. Exemplary heteroaryl systems are derivedfrom, but not limited to, the following ring systems: pyrrole, furan,thiophene, imidazole, pyrazole, oxazole (=[1,3]oxazole), isoxazole(=[1,2]oxazole), thiazole (=[1,3]thiazole), isothiazole(=[1,2]thiazole), [1,2,3]triazole, [1,2,4]triazole, [1,2,4]oxadiazole,[1,3,4]oxadiazole, [1,2,4]thiadiazole, [1,3,4]thiadiazole, tetrazole,pyridine, pyridazine, pyrimidine, pyrazine, [1,2,3]triazine,[1,2,4]triazine, [1,3,5]triazine, indole, isoindole, benzofuran,benzothiophene [1,3]benzoxazole, [1,3]benzothiazole, benzoimidazole,indazole, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline,phthalazine, different naphthyridines, e.g. [1,8]naphthyridine,different thienopyridines, e.g. thieno[2,3-b]pyridine and purine.

The term “heterocyclyl” refers to a nonaromatic 5-8 membered monocyclic,8-12 membered bicyclic, or 11-14 membered tricyclic ring system having1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S(e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S ifmonocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3atoms of each ring may be substituted by a substituent. Examples ofheterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl,morpholinyl, tetrahydrofuranyl, and the like.

In addition, atoms making up the compounds of the present embodimentsare intended to include all isotopic forms of such atoms. Isotopes, asused herein, include those atoms having the same atomic number butdifferent mass numbers. By way of general example and withoutlimitation, isotopes of hydrogen include tritium and deuterium, andisotopes of carbon include ¹³C and ¹⁴C.

The compounds provided herein may encompass various stereochemicalforms. The compounds also encompass diastereomers as well as opticalisomers, e.g., mixtures of enantiomers (including atropisomers)including racemic mixtures, as well as individual enantiomers anddiastereomers, which arise as a consequence of structural asymmetry incertain compounds. Separation of the individual isomers or selectivesynthesis of the individual isomers is accomplished by application ofvarious methods which are well known to practitioners in the art. Unlessotherwise indicated, when a disclosed compound is named or depicted by astructure without specifying the stereochemistry and has one or morechiral centers, it is understood to represent all possible stereoisomersof the compound. For example, —S(O)(═NH)—R⁴ is intended to encompassenantiomer:

and enantiomer:

as well as a mixture thereof (e.g., racemic mixture).

The details of one or more embodiments of the invention are set forth inthe description below and in the accompanying Appendix, which isexpressly considered part of this disclosure. Other features andadvantages will also be apparent from the claims.

DETAILED DESCRIPTION

This disclosure features chemical entities (e.g., a compound or apharmaceutically acceptable salt and/or hydrate and/or prodrug of thecompound) that modulate (e.g., agonize) the apelin receptor (alsoreferred to herein as the APJ receptor; gene symbol “APLNR”). Thisdisclosure also features compositions containing the same as well asother methods of using and making the same. The chemical entities areuseful, e.g., for treating a subject (e.g., a human) having a disease,disorder, or condition in which a decrease in APJ receptor activity(e.g., repressed or impaired APJ receptor signaling; e.g., repressed orimpaired apelin-APJ receptor signaling) or downregulation of endogenousapelin contributes to the pathology and/or symptoms and/or progressionof the disease, disorder, or condition. Non-limiting examples of suchdiseases, disorders, or conditions include: (i) cardiovascular disease;(ii) metabolic disorders; (iii) diseases, disorders, and conditionsassociated with vascular pathology; and (iv) organ failure; (v)diseases, disorders, and conditions associated with infections (e.g.,microbial infections); and (vi) diseases, disorders, or conditions thatare sequela or comorbid with any of the foregoing or any disclosedherein. More particular non-limiting examples of such diseases,disorders, or conditions include pulmonary hypertension (e.g., PAH);heart failure; type II diabetes; renal failure; sepsis; and systemichypertension.

Formula (I) Compounds

In one aspect, this disclosure features compounds of Formula (I), or apharmaceutically acceptable salt thereof:

or a pharmaceutically acceptable salt thereof;wherein:A¹ is CH or N;each of X¹, X², X³, and X⁴ is independently selected from the groupconsisting of N and CR³;R¹ is:(i) —(Y¹)_(n)—Y², wherein:

-   -   n is 0 or 1;    -   Y¹ is C₁₋₆ alkylene, which is optionally substituted with from        1-6 R^(a); and    -   Y² is:        -   (a) C₃₋₁₀ cycloalkyl, which is optionally substituted with            from 1-4 R^(b);        -   (b) C₆₋₁₀ aryl, which is optionally substituted with from            1-4 R^(c);        -   (c) heteroaryl including from 5-10 ring atoms, wherein from            1-4 ring atoms are heteroatoms, each independently selected            from the group consisting of N, N(H), N(R^(d)), O, and S,            and wherein one or more of the heteroaryl ring carbon atoms            are optionally substituted with from 1-4 independently            selected R^(c), or        -   (d) heterocyclyl including from 3-10 ring atoms, wherein            from 1-3 ring atoms are heteroatoms, each independently            selected from the group consisting of N, N(H), N(R^(d)), and            O, and wherein one or more of the heterocyclyl ring carbon            atoms are optionally substituted with from 1-4 independently            selected R^(b),            OR            (ii) —Z¹—Z²—Z³, wherein:    -   Z¹ is C₁₋₃ alkylene, which is optionally substituted with from        1-4 R^(a);    -   Z² is —N(H)—, —N(R^(d))—, —O—, or —S—; and    -   Z³ is C₂₋₇ alkyl, which is optionally substituted with from 1-4        R^(a);        OR        (iii) C₃₋₁₀ alkyl, optionally substituted with from 1-6        independently selected R^(a);        OR        (iv) —Z⁴—Z⁵—Z⁶—Y² wherein:    -   Z⁴ is C₁₋₃ alkylene, which is optionally substituted with from        1-4 R^(a);    -   Z⁵ is —N(H)—, —N(R^(d))—, —O—, or —S—;    -   Z⁶ is C₁₋₄ alkylene, which is optionally substituted with from        1-4 R^(a); and    -   Y² is as defined above;        R² is:    -   (i) C₆₋₁₀ aryl, which is optionally further substituted with        from 1-4 R^(c);    -   (ii) heteroaryl including from 5-10 ring atoms, wherein from 1-4        ring atoms are heteroatoms, each independently selected from the        group consisting of N, N(H), N(R^(d)), O, and S, and wherein one        or more of the heteroaryl ring carbon atoms are optionally        substituted with from 1-4 independently selected R^(c);    -   (iii) C₃₋₁₀ cycloalkyl, which is optionally substituted with        from 1-4 R^(b);    -   (iv) heterocyclyl including from 3-10 ring atoms, wherein from        1-3 ring atoms are heteroatoms, each independently selected from        the group consisting of N, N(H), N(R^(d)), and O, and wherein        one or more of the heterocyclyl ring carbon atoms are optionally        substituted with from 1-4 independently selected R^(b); or    -   (v) C₁₋₁₀ alkyl, which is optionally substituted with from 1-6        independently selected R^(a);    -   each occurrence of R³ is independently selected from the group        consisting of -L⁴-R⁴, H and, R^(c′);        each occurrence of L⁴ is independently selected from the group        consisting of:    -   (i) a single bond;    -   (ii) N(H), N(R^(d)), or N(R⁴);    -   (iii) —N(H)S(O)₁₋₂— or —N(R^(d))S(O)₁₋₂—;    -   (iv) —S(O)₁₋₂N(H)— or —S(O)₁₋₂N(R^(d))—;    -   (v) —O—;    -   (vi) —S(O)₀₋₂—;    -   (vii) —C(O)NH— or —C(O)N(R^(d))    -   (viii) —N(H)C(O)— or —N(R^(d))C(O)—;    -   (ix) —C≡C;    -   (x) —N(H)S(O)(═NH)—, —N(R^(d))S(O)(═NH), —N(H)S(O)(═NR^(d))—, or        —N(R^(d))S(O)(═NR^(d))—    -   (xi) —S(O)(═NH)NH—, —S(O)(═NR^(d))NH—, —S(O)(═NH)NR^(d)—, or        —S(O)(═NR^(d))NR^(d)—;    -   (xii) —S(O)(═NH)— or —S(O)(═NR^(d)); and    -   (xiii) —N(H)S(O)₁₋₂N(H)—, —N(R^(d))S(O)₁₋₂N(H)—,        —N(H)S(O)₁₋₂N(R^(d))—, or —N(R^(d))S(O)₁₋₂N(R^(d))—;        each occurrence of R⁴ is, independently:    -   (i) —(Y³)_(p)—Y⁴, wherein:        -   p is 0 or 1;        -   Y³ is C₁₋₆ alkylene or C₁₋₆ alkenylene, each of which is            optionally substituted with from 1-6 R^(a); and        -   Y⁴ is:            -   (a) C₃₋₆ cycloalkyl, which is optionally substituted                with from 1-4 R^(b),            -   (b) C₆₋₁₀ aryl, which is optionally substituted with                from 1-4 R^(c);            -   (c) heteroaryl including from 5-10 ring atoms, wherein                from 1-4 ring atoms are heteroatoms, each independently                selected from the group consisting of N, N(H), N(R^(d)),                O, and S, and wherein one or more of the heteroaryl ring                carbon atoms are optionally substituted with from 1-4                independently selected R^(c), or            -   (d) heterocyclyl including from 3-10 ring atoms, wherein                from 1-3 ring atoms are heteroatoms, each independently                selected from the group consisting of N, N(H), N(R^(d)),                and O, and wherein one or more of the heterocyclyl ring                carbon atoms are optionally substituted with from 1-4                independently selected R^(b),                OR    -   (ii) C₁₋₁₀ alkyl, C₁₋₁₀ alkenyl, or C₁₋₁₀ alkynyl, each of which        is optionally substituted with from 1-6 independently selected        R^(a);        each occurrence of R^(a) is independently selected from the        group consisting of: —OH; —F; —Cl; —Br; —NR^(e)R^(f); C₁₋₄        alkoxy; C₁₋₄ haloalkoxy; —C(═O)O(C₁₋₄ alkyl); —C(═O)(C₁₋₄        alkyl); —C(═O)OH; —CON(R′)(R″); —S(O)₁₋₂(NR′R″); —S(O)₁₋₂(C₁₋₄        alkyl); cyano, and C₃₋₆ cycloalkyl optionally substituted with        from 1-4 independently selected C₁₋₄ alkyl;        each occurrence of R^(b) is independently selected from the        group consisting of: C₁₋₆ alkyl; C₁₋₄ haloalkyl; —OH; oxo; —F;        —Cl; —Br; —NR^(e)R^(f); C₁₋₄ alkoxy; C₁₋₄ haloalkoxy;        —C(═O)(C₁₋₄ alkyl); —C(═O)O(C₁₋₄ alkyl); —C(═O)OH;        —C(═O)N(R′)(R″); —S(O)₁₋₂(NR′R″); —S(O)₁₋₂(C₁₋₄ alkyl); cyano;        and C₃₋₆ cycloalkyl optionally substituted with from 1-4        independently selected C₁₋₄ alkyl;        each occurrence of R^(c) is independently selected from the        group consisting of:        (i) halo;        (ii) cyano;        (iii) C₁₋₆ alkyl;        (iv) C₂₋₆ alkenyl;        (v) C₂₋₆ alkynyl;        (vi) C₁₋₄ haloalkyl;        (vii) C₁₋₄ alkoxy;        (viii) C₁₋₄ haloalkoxy;        (ix) —(C₀₋₃ alkylene)-C₃₋₆ cycloalkyl optionally substituted        with from 1-4 independently selected C₁₋₄ alkyl;        (x) —S(O)₁₋₂(C₁₋₄ alkyl);        (xi) —NR^(e)R^(f);        (xii) —OH;        (xiii) —S(O)₁₋₂(NR′R″);        (xiv) —C₁₋₄ thioalkoxy;        (xv) —NO₂;        (xvi) —C(═O)(C₁₋₄ alkyl);        (xvii) —C(═O)O(C₁₋₄ alkyl);        (xviii) —C(═O)OH,        (xix) —C(═O)N(R′)(R″), and        (xx) C₃₋₆ cycloalkoxy;        each occurrence of R^(c′) is independently selected from the        group consisting of:        (i) halo;        (ii) cyano;        (iii) —OH;        (iv) —NO₂;        (v) —C(═O)(C₁₋₄ alkyl);        (vi) —C(═O)O(C₁₋₄ alkyl);        (vii) —C(═O)OH; and        (viii) —NH₂;        R^(d) is selected from the group consisting of: C₁₋₆ alkyl; C₃₋₆        cycloalkyl; —C(O)(C₁₋₄ alkyl); —C(O)O(C₁₋₄ alkyl); —CON(R′)(R″);        —S(O)₁₋₂(NR′R″); —S(O)₁₋₂(C₁₋₄ alkyl); —OH; and C₁₋₄ alkoxy;        each occurrence of R^(e) and R^(f) is independently selected        from the group consisting of: H; C₁₋₆ alkyl; C₃₋₆ cycloalkyl;        —C(O)(C₁₋₄ alkyl); —C(O)O(C₁₋₄ alkyl); —CON(R′)(R″);        —S(O)₁₋₂(NR′R″); —S(O)₁₋₂(C₁₋₄ alkyl); —OH; and C₁₋₄ alkoxy; or        R^(e) and R^(f) together with the nitrogen atom to which each is        attached forms a ring including from 3-8 ring atoms, wherein the        ring includes: (a) from 1-7 ring carbon atoms, each of which is        substituted with from 1-2 substituents independently selected        from H and C₁₋₃ alkyl; and (b) from 0-3 ring heteroatoms (in        addition to the nitrogen atom attached to R′ and R″), which are        each independently selected from the group consisting of        N(R^(d)), O, and S; and        each occurrence of R′ and R″ is independently selected from the        group consisting of: H and C₁₋₄ alkyl; or R′ and R″ together        with the nitrogen atom to which each is attached forms a ring        including from 3-8 ring atoms, wherein the ring includes: (a)        from 1-7 ring carbon atoms, each of which is substituted with        from 1-2 substituents independently selected from H and C₁₋₃        alkyl; and (b) from 0-3 ring heteroatoms (in addition to the        nitrogen atom attached to R′ and R″), which are each        independently selected from the group consisting of N(R^(d)), O,        and S.

In some embodiments, this disclosure features compounds of Formula (I),or a pharmaceutically acceptable salt thereof:

wherein:

A¹ is CH or N;

each of X¹, X², X³, and X⁴ is independently selected from the groupconsisting of N and CR³ (e.g., each of X¹ and X⁴ is independently CH orN; and each of X² and X³ is independently CR³ or N), provided that from1-3 of X¹, X², X³, and X⁴ is N;

R¹ is:

(i) —(Y¹)_(n)—Y², wherein:

-   -   n is 0 or 1;    -   Y¹ is C₁₋₆ alkylene, which is optionally substituted with from        1-6 R^(a); and    -   Y² is:        -   (a) C₃₋₁₀ cycloalkyl, which is optionally substituted with            from 1-4 R^(b),        -   (b) C₆₋₁₀ aryl, which is optionally substituted with from            1-4 R^(c);        -   (c) heteroaryl including from 5-10 ring atoms, wherein from            1-4 ring atoms are heteroatoms, each independently selected            from the group consisting of N, N(H), N(R^(d)), O, and S,            and wherein one or more of the heteroaryl ring carbon atoms            are optionally substituted with from 1-4 independently            selected R^(c), or        -   (d) heterocyclyl including from 3-10 ring atoms, wherein            from 1-3 ring atoms are heteroatoms, each independently            selected from the group consisting of N, N(H), N(R^(d)), and            O, and wherein one or more of the heterocyclyl ring carbon            atoms are optionally substituted with from 1-4 independently            selected R^(b),

OR

(ii) —Z¹—Z²—Z³, wherein:

-   -   Z¹ is C₁₋₃ alkylene, which is optionally substituted with from        1-4 R^(a);    -   Z² is —N(H)—, —N(R^(d))—, —O—, or —S—; and    -   Z³ is C₂₋₇ alkyl, which is optionally substituted with from 1-4        R^(a);

OR

(iii) C₃₋₁₀ alkyl, optionally substituted with from 1-6 independentlyselected R^(a);

OR

(iv) —Z⁴—Z⁵—Z⁶—Y² wherein:

-   -   Z⁴ is C₁₋₃ alkylene, which is optionally substituted with from        1-4 R^(a);    -   Z⁵ is —N(H)—, —N(R^(d))—, —O—, or —S—;    -   Z⁶ is C₁₋₄ alkylene, which is optionally substituted with from        1-4 R^(a); and    -   Y² is as defined above;

R² is:

(i) C₆₋₁₀ aryl, which is optionally further substituted with from 1-4R^(c);

(ii) heteroaryl including from 5-10 ring atoms, wherein from 1-4 ringatoms are heteroatoms, each independently selected from the groupconsisting of N, N(H), N(R^(d)), O, and S, and wherein one or more ofthe heteroaryl ring carbon atoms are optionally substituted with from1-4 independently selected R^(c);

(iii) C₃₋₁₀ cycloalkyl, which is optionally substituted with from 1-4R^(b);

(iv) heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ringatoms are heteroatoms, each independently selected from the groupconsisting of N, N(H), N(R^(d)), and O, and wherein one or more of theheterocyclyl ring carbon atoms are optionally substituted with from 1-4independently selected R^(b); or

(v) C₁₋₁₀ alkyl, which is optionally substituted with from 1-6independently selected R^(a)

each occurrence of R³ is independently selected from the groupconsisting of -L⁴-R⁴, H and, R^(c′);

each occurrence of L⁴ is independently selected from the groupconsisting of:

-   -   (i) a single bond;    -   (ii) N(H), N(R^(d)), or N(R⁴);    -   (iii) —N(H)S(O)₁₋₂— or —N(R^(d))S(O)₁₋₂—;    -   (iv) —S(O)₁₋₂N(H)— or —S(O)₁₋₂N(R^(d))—;    -   (v) —O—;    -   (vi) —S(O)₀₋₂—;    -   (vii) —C(O)NH— or —C(O)N(R^(d));    -   (viii) —N(H)C(O)— or —N(R^(d))C(O)—;    -   (ix) —C≡C;    -   (x) —N(H)S(O)(═NH)—, —N(R^(d))S(O)(═NH), —N(H)S(O)(═NR^(d))—, or        —N(R^(d))S(O)(═NR^(d))—    -   (xi) —S(O)(═NH)NH—, —S(O)(═NR^(d))NH—, —S(O)(═NH)NR^(d)—, or        —S(O)(═NR^(d))NR^(d)—; and    -   (xii) —S(O)(═NH)— or —S(O)(═NR^(d));

each occurrence of R′ is, independently:

-   -   (i) —(Y³)_(p)—Y⁴, wherein:        -   p is 0 or 1;        -   Y³ is C₁₋₆ alkylene or C₁₋₆ alkenylene, each of which is            optionally substituted with from 1-6 R^(a); and        -   Y⁴ is:            -   (a) C₃₋₆ cycloalkyl, which is optionally substituted                with from 1-4 R^(b),            -   (b) C₆₋₁₀ aryl, which is optionally further substituted                with from 1-4 R^(c);            -   (c) heteroaryl including from 5-10 ring atoms, wherein                from 1-4 ring atoms are heteroatoms, each independently                selected from the group consisting of N, N(H), N(R^(d)),                O, and S, and wherein one or more of the heteroaryl ring                carbon atoms are optionally substituted with from 1-4                independently selected R^(c), or            -   (d) heterocyclyl including from 3-10 ring atoms, wherein                from 1-3 ring atoms are heteroatoms, each independently                selected from the group consisting of N, N(H), N(R^(d)),                and O, and wherein one or more of the heterocyclyl ring                carbon atoms are optionally substituted with from 1-4                independently selected R^(b),

OR

(ii) C₁₋₁₀ alkyl, C₁₋₁₀ alkenyl, or C₁₋₁₀ alkynyl, each of which isoptionally substituted with from 1-6 independently selected R^(a);

each occurrence of R^(a) is independently selected from the groupconsisting of: —OH; —F; —Cl; —Br; —NR^(e)R^(f); C₁₋₄ alkoxy; C₁₋₄haloalkoxy; —C(═O)O(C₁₋₄ alkyl); —C(═O)(C₁₋₄ alkyl); —C(═O)OH;—CON(R′)(R″); —S(O)₁₋₂(NR′R″); —S(O)₁₋₂(C₁₋₄ alkyl); cyano, and C₃₋₆cycloalkyl optionally substituted with from 1-4 independently selectedC₁₋₄ alkyl;

each occurrence of R^(b) is independently selected from the groupconsisting of: C₁₋₆ alkyl; C₁₋₄ haloalkyl; —OH; oxo; —F; —Cl; —Br;—NR^(e)R^(f); C₁₋₄ alkoxy; C₁₋₄ haloalkoxy; —C(═O)(C₁₋₄ alkyl);—C(═O)O(C₁₋₄ alkyl); —C(═O)OH; —C(═O)N(R′)(R″); —S(O)₁₋₂(NR′R″);—S(O)₁₋₂(C₁₋₄ alkyl); cyano; and C₃₋₆ cycloalkyl optionally substitutedwith from 1-4 independently selected C₁₋₄ alkyl;

each occurrence of R^(c) is independently selected from the groupconsisting of:

(i) halo;

(ii) cyano;

(iii) C₁₋₆ alkyl;

(iv) C₂₋₆ alkenyl;

(v) C₂₋₆ alkynyl;

(vi) C₁₋₄ haloalkyl;

(vii) C₁₋₄ alkoxy;

(viii) C₁₋₄ haloalkoxy;

(ix) —(C₀₋₃ alkylene)-C₃₋₆ cycloalkyl optionally substituted with from1-4 independently selected C₁₋₄ alkyl;

(x) —S(O)₁₋₂(C₁₋₄ alkyl);

(xi) —NR^(e)R^(f);

(xii) —OH;

(xiii) —S(O)₁₋₂(NR′R″);

(xiv) —C₁₋₄ thioalkoxy;

(xv) —NO₂;

(xvi) —C(═O)(C₁₋₄ alkyl);

(xvii) —C(═O)O(C₁₋₄ alkyl);

(xviii) —C(═O)OH;

(xix) —C(═O)N(R′)(R″); and

(xx) C₃₋₆ cycloalkoxy;

each occurrence of R^(c′) is independently selected from the groupconsisting of:

(i) halo;

(ii) cyano;

(iii) —OH;

(iv) —NO₂;

(v) —C(═O)(C₁₋₄ alkyl);

(vi) —C(═O)O(C₁₋₄ alkyl);

(vii) —C(═O)OH; and

(viii) —NH₂;

R^(d) is selected from the group consisting of: C₁₋₆ alkyl; C₃₋₆cycloalkyl; —C(O)(C₁₋₄ alkyl); —C(O)O(C₁₋₄ alkyl); —CON(R′)(R″);—S(O)₁₋₂(NR′R″); —S(O)₁₋₂(C₁₋₄ alkyl); —OH; and C₁₋₄ alkoxy;

each occurrence of R^(e) and R^(f) is independently selected from thegroup consisting of: H; C₁₋₆ alkyl; C₃₋₆ cycloalkyl; —C(O)(C₁₋₄ alkyl);—C(O)O(C₁₋₄ alkyl); —CON(R′)(R″); —S(O)₁₋₂(NR′R″); —S(O)₁₋₂(C₁₋₄ alkyl);—OH; and C₁₋₄ alkoxy; or R^(e) and R^(f) together with the nitrogen atomto which each is attached forms a ring including from 3-8 ring atoms,wherein the ring includes: (a) from 1-7 ring carbon atoms, each of whichis substituted with from 1-2 substituents independently selected from Hand C₁₋₃ alkyl; and (b) from 0-3 ring heteroatoms (in addition to thenitrogen atom attached to R′ and R″), which are each independentlyselected from the group consisting of N(R^(d)), O, and S; and

each occurrence of R′ and R″ is independently selected from the groupconsisting of: H and C₁₋₄ alkyl; or R′ and R″ together with the nitrogenatom to which each is attached forms a ring including from 3-8 ringatoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, eachof which is substituted with from 1-2 substituents independentlyselected from H and C₁₋₃ alkyl; and (b) from 0-3 ring heteroatoms (inaddition to the nitrogen atom attached to R′ and R″), which are eachindependently selected from the group consisting of N(R^(d)), O, and S.

In some embodiments, it is provided that when the compound is of Formula(I-1):

R¹ is other than unsubstituted phenyl, para-dimethylaminophenyl,para-aminosulfonylphenyl, and unsubstituted 4-pyridinyl.

In some embodiments, it is provided that when the compound of of Formula(I-1):

R¹ is other than unsubstituted phenyl, para-mono-substituted phenyl, andunsubstituted pyridinyl.

In some embodiments, it is provided that when the compound of Formula(I-2):

R¹ is other than unsubstituted phenyl.

In some embodiments, it is provided that the compound is other than acompound of Formula (I-1) or Formula (I-2):

In some embodiments, it is provided that the compound is not of Formula(I-3):

In some embodiments, it is provided that when the compound is of Formula(I-4):

R¹ is other than para-monosubstituted phenyl (e.g., para-fluorophenyl).

In some embodiments, it is provided that when the compound is of Formula(I-5):

R³ is other than trifluoromethyl.

In some embodiments, it is provided that when the compound is of Formula(I-6):

R² is other than:

-   -   (i) unsubstituted phenyl;

-   -   (iv) unsubstituted pyridinyl;

wherein each of Q¹, Q², Q³, and Q⁴ is independently selected from N andCH; or

-   -   (vi) heteroaryl including from 9-10 ring atoms, wherein from 1-2        ring atoms are heteroatoms, each independently selected from the        group consisting of N, N(H), N(R^(d)), O, and S, and wherein one        or more of the heteroaryl ring carbon atoms are optionally        substituted with from 1-2 independently selected R^(c).

In some embodiments, the compound is other than one or more of thefollowing:

In some embodiments, the compound is other than one or more of thefollowing:

In certain embodiments, the compound is other than those disclosed inEuropean Journal of Medicinal Chemistry (2014), 86, 270-278. In certainembodiments, the compound is other than those disclosed in TetrahedronLetters (2012), 53(25), 3126-3130. In certain embodiments, the compoundis other than those disclosed in Organic Letters (2011), 13(24),6516-6519. In certain embodiments, the compound is other than thosedisclosed in U.S. Patent Application Publication No. 2012/0095037 and/orU.S. Pat. No. 8,362,019.

In certain embodiments, the compound is other than those disclosed inAngewandte Chemie, International Edition (2018), 57(5), 1399-1403. Incertain embodiments, the compound is other than those disclosed inOrganic Letters (2017), 19(19), 5118-5121. In certain embodiments, thecompound is other than those disclosed in Tetrahedron (2009), 65(44),8930-8939. In certain embodiments, the compound is other than thosedisclosed in Organic Letters (2016), 18(13), 3250-3253. In certainembodiments, the compound is other than those disclosed in Organic &Biomolecular Chemistry (2015), 13(21), 6047-6058. In certainembodiments, the compound is other than those disclosed in Chemistry—AEuropean Journal (2013), 19(49), 16760-16771. In certain embodiments,the compound is other than those disclosed in Organic & BiomolecularChemistry (2013), 11(18), 3064-3072. In certain embodiments, thecompound is other than those disclosed in Organic Letters (2011),13(24), 6516-6519. In certain embodiments, the compound is other thanthose disclosed in Bioorganic & Medicinal Chemistry Letters (2004),14(13), 3595-3599. In certain embodiments, the compound is other thanthose disclosed in International Patent Application Publication No.2015/073528. In certain embodiments, the compound is other than thosedisclosed in International Patent Application Publication No.2012/146667. In certain embodiments, the compound is other than thosedisclosed in International Patent Application Publication No.2001/030778. In certain embodiments, the compound is other than thosedisclosed in U.S. Patent Application Publication No. 2012/0095037.

In certain embodiments, the compound is other than those disclosed inJournal of Medicinal Chemistry (2012), 55(11), 5291-5310. In certainembodiments, the compound is other than those disclosed in TetrahedronLetters (2000), 41(28), 5383-5386. In certain embodiments, the compoundis other than those disclosed in International Patent ApplicationPublication No. WO 2017/171234. In certain embodiments, the compound isother than those disclosed in International Patent ApplicationPublication No. WO 2016/176460. In certain embodiments, the compound isother than those disclosed in Japanese Patent Application PublicationNo. JP 2013/018771 and/or JP 5,959,330. In certain embodiments, thecompound is other than those disclosed in International PatentApplication Publication No. WO 2011/153310. In certain embodiments, thecompound is other than those disclosed in International PatentApplication Publication No. WO 2011/082270. In certain embodiments, thecompound is other than those disclosed in Australia Patent ApplicationPublication No. AU 2010/331175 and/or U.S. Patent ApplicationPublication No. US 2012/0258951 and/or U.S. 2014/0194407. In certainembodiments, the compound is other than those disclosed in InternationalPatent Application Publication No. WO 2010/051245 and/or U.S. PatentApplication Publication No. US 2011/0207750. In certain embodiments, thecompound is other than those disclosed in WO 2010/030360. In certainembodiments, the compound is other than those disclosed in EuropeanPatent Application No. EP 1878724 and/or U.S. Pat. No. 8,188,282. Incertain embodiments, the compound is other than those disclosed inInternational Patent Application No. WO 2007/075629. In certainembodiments, the compound is other than those disclosed in Japan PatentApplication Publication No. JP 2000/302754 and/or U.S. Pat. No.6,358,634.

Variable A¹ and X¹-X⁴

In some embodiments, A¹ is N.

In other embodiments, A¹ is CH.

In some embodiments, each of X¹ and X⁴ is independently selected from CHand N.

In some embodiments, from 1-2 of X¹, X², X³, and X⁴ are independently N.

In certain embodiments from 1-2 of X¹, X², X³, and X⁴ are independentlyN; and from 2-3 of X¹, X², X³, and X⁴ are each an independently selectedCR³.

In certain embodiments, from 1-2 of X¹, X², X³, and X⁴ are independentlyN; and each of X¹ and X⁴ is independently N or CH.

In some embodiments, two of X¹, X², X³, and X⁴ are independently N; andthe other two of X¹, X², X³, and X⁴ are independently selected from Nand CR³.

In certain embodiments, a compound of Formula (I) is of Formula (I-a):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of Formula (I) is of Formula (I-b):

or a pharmaceutically acceptable salt thereof.

In certain of the foregoing embodiments when two of X¹, X², X³, and X⁴are independently N, the other two of X¹, X², X³, and X⁴ areindependently selected CR³.

In certain embodiments, a compound of Formula (I) is of Formula (I-a1):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of Formula (I) is of Formula (I-a2):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of Formula (I) is of Formula (I-b1):

or a pharmaceutically acceptable salt thereof.

In some embodiments, one of X¹, X², X³, and X⁴ is independently N; andthe other three of X¹, X², X³, and X⁴ are independently selected from Nand CR³.

In certain embodiments, a compound of Formula (I) is of Formula (I-c):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of Formula (I) is of Formula (I-d):

or a pharmaceutically acceptable salt thereof.

In certain of the foregoing embodiments when one of X¹, X², X³, and X⁴is independently N, the other three of X¹, X², X³, and X⁴ areindependently selected CR³.

In certain embodiments, a compound of Formula (I) is of Formula (I-c1):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of Formula (I) is of Formula (I-d1):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I-d1) has the followingformula:

wherein: one R³ is independently selected from -L⁴-R⁴ and R^(c′);

the other R³ is independently selected from H, -L⁴-R⁴, and R^(c′);

R¹ is (i) —(Y¹)_(n)—Y², wherein:

-   -   n is 0;    -   Y² is:        -   (a) partially unsaturated C₃₋₁₀ cycloalkyl, which is            optionally substituted with from 1-4 R^(b),        -   (b) C₆₋₁₀ aryl, which is optionally substituted with from            1-4 R^(c);        -   (c) heteroaryl including from 5-10 ring atoms, wherein from            1-4 ring atoms are heteroatoms, each independently selected            from the group consisting of N, N(H), N(R^(d)), O, and S,            and wherein one or more of the heteroaryl ring carbon atoms            are optionally substituted with from 1-4 independently            selected R^(c), or        -   (d) partially unsaturated heterocyclyl including from 3-10            ring atoms, wherein from 1-3 ring atoms are heteroatoms,            each independently selected from the group consisting of N,            N(H), N(R^(d)), and O, and wherein one or more of the            heterocyclyl ring carbon atoms are optionally substituted            with from 1-4 independently selected R^(b); and

R² is:

(i) C₆₋₁₀ aryl, which is optionally further substituted with from 1-4R^(c);

(ii) heteroaryl including from 5-10 ring atoms, wherein from 1-4 ringatoms are heteroatoms, each independently selected from the groupconsisting of N, N(H), N(R^(d)), O, and S, and wherein one or more ofthe heteroaryl ring carbon atoms are optionally substituted with from1-4 independently selected R^(c);

(iii) partially unsaturated C₃₋₁₀ cycloalkyl, which is optionallysubstituted with from 1-4 R^(b); or

(iv) partially unsaturated heterocyclyl including from 3-10 ring atoms,wherein from 1-3 ring atoms are heteroatoms, each independently selectedfrom the group consisting of N, N(H), N(R^(d)), and O, and wherein oneor more of the heterocyclyl ring carbon atoms are optionally substitutedwith from 1-4 independently selected R^(b).

Variable R¹

In some embodiments, R¹ is —(Y¹)_(n)—Y².

In some embodiments, n is 0.

In other embodiments, n is 1. In certain of these embodiments, Y¹ isC₁₋₃ alkylene.

In some embodiments, Y² is heteroaryl including from 5-10 ring atoms,wherein from 1-4 ring atoms are heteroatoms, each independently selectedfrom the group consisting of N, N(H), N(R^(d)), O, and S, and whereinone or more of the heteroaryl ring carbon atoms are optionallysubstituted with from 1-4 independently selected R^(c). In certain ofthe foregoing embodiments, n is 0.

In some embodiments, Y² is heteroaryl including from 6 ring atoms,wherein from 1-4 ring atoms are heteroatoms, each independently selectedfrom the group consisting of N, N(H), N(R^(d)), O, and S, and whereinone or more of the heteroaryl ring carbon atoms are substituted withfrom 1-4 independently selected R^(c); or heteroaryl including 5 or from9-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, eachindependently selected from the group consisting of N, N(H), N(R^(d)),O, and S, and wherein one or more of the heteroaryl ring carbon atomsare optionally substituted with from 1-4 independently selected R^(c);In certain of the foregoing embodiments, n is 0.

In certain embodiments, Y² is heteroaryl including from 5-6 ring atoms,wherein from 1-4 ring atoms are heteroatoms, each independently selectedfrom the group consisting of N, N(H), N(R^(d)), O, and S, and whereinone or more of the heteroaryl ring carbon atoms are optionallysubstituted with from 1-4 independently selected R^(c). In certain ofthese embodiments, n is 0.

In certain embodiments, Y² is heteroaryl including 6 ring atoms, whereinfrom 1-2 ring atoms are N, and wherein one or more of the heteroarylring carbon atoms are optionally substituted with from 1-4 independentlyselected R^(c). For example, Y² can be pyridyl (e.g., 2-pyridyl or6-pyridyl), wherein one or more of the ring carbon atoms are optionallysubstituted with from 1-4 (e.g., 1, 2, 3, or 4) independently selectedR^(c) (e.g., Y² is pyridyl (e.g., 2-pyridyl or 6-pyridyl), wherein oneor more of the ring carbon atoms are optionally substituted with oneindependently selected R^(c)). In certain of these embodiments, n is 0.

In certain embodiments, Y² is heteroaryl including 5 ring atoms, whereinfrom 1-4 ring atoms are heteroatoms, each independently selected fromthe group consisting of N, N(H), N(R^(d)), O, and S, and wherein one ormore of the heteroaryl ring carbon atoms are optionally substituted withfrom 1-2 independently selected R^(c). For example, Y² can be pyrazolyl,oxazolyl, or thiazolyl, wherein any substitutable nitrogen atom isoptionally substituted with R^(d), and wherein one or more of the ringcarbon atoms are optionally substituted with from 1-2 independentlyselected R^(c). In certain of these embodiments, n is 0.

In certain embodiments, Y² is heteroaryl including 5 ring atoms, whereinfrom 1-3 ring atoms are heteroatoms, each independently selected fromthe group consisting of N, N(H), N(R^(d)), O, and S, and wherein one ormore of the heteroaryl ring carbon atoms are optionally substituted withfrom 1-3 independently selected R^(c). In certain of these embodiments,n is 0.

In certain of these embodiments, Y² is furanyl, wherein one or more ofthe ring carbon atoms are optionally substituted with from 1-2 (e.g., 1)independently selected R^(c).

In certain of these embodiments, n is 0.

In certain of the foregoing embodiments when Y² is heteroaryl, eachoccurrence of R^(c) is independently selected from the group consistingof:

(iii) C₁₋₆ alkyl;

(iv) C₂₋₆ alkenyl;

(v) C₂₋₆ alkynyl;

(vi) C₁₋₄ haloalkyl;

(vii) C₁₋₄ alkoxy;

(viii) C₁₋₄ haloalkoxy;

(ix) —(C₀₋₃ alkylene)-C₃₋₆ cycloalkyl optionally substituted with from1-4 independently selected C₁₋₄ alkyl;

(xiv) —C₁₋₄ thioalkoxy;

and

(xx) C₃₋₆ cycloalkoxy.

In certain of the foregoing embodiments when Y² is heteroaryl, eachoccurrence of R^(c) is independently selected from the group consistingof:

(vii) C₁₋₄ alkoxy;

(viii) C₁₋₄ haloalkoxy (e.g., OCH₂CF₃ or OCF₃);

(xiv) —C₁₋₄ thioalkoxy; and

(xx) C₃₋₆ cycloalkoxy (e.g., cyclopropoxy).

For example, each occurrence of R^(c) is an independently selected C₁₋₄alkoxy (e.g., —OCH₃, —OCH₂CH₃).

As another example, each occurrence of R^(c) is an independentlyselected C₁₋₆ alkyl (e.g., methyl).

In certain of the foregoing embodiments when Y² is heteroaryl, eachoccurrence of R^(d) is an independently selected C₁₋₆ alkyl.

In certain of the foregoing embodiments when Y² is heteroaryl and n is0, R¹ can be selected from the group consisting of:

In certain of the foregoing embodiments when Y² is heteroaryl and n is0, R¹ can be selected from the group consisting of:

As a non-limiting example of the foregoing embodiments, when Y² isheteroaryl and n is 0, R¹ can be:

In certain embodiments, when Y² is heteroaryl and n is 0, R¹ can be:

In certain embodiments, when Y² is heteroaryl and n is 0, R¹ can be:

In some embodiments, Y² is C₃₋₁₀ cycloalkyl, which is optionallysubstituted with from 1-4 R^(b). In certain of these embodiments, n is0.

In some embodiments, Y² is C₆₋₁₀ aryl, which is optionally substitutedwith from 1-4 R^(c).

In certain embodiments, Y² is phenyl, which is substituted with from 1-4R^(c).

In certain embodiments when Y² is phenyl; and the ring carbon atom parato the point of attachment to Y¹ is substituted with R^(c), then one ormore of the other ring carbon atoms is optionally substituted with from1-3 R^(c).

In some embodiments, R¹ is —Z¹—Z²—Z³.

In some embodiments, Z¹ is CH₂.

In some embodiments, Z² is —O—, or —S—. For example, Z² can be —O—.

In some embodiments, Z³ is C₂₋₃ alkylene.

In certain embodiments, Z¹ is CH₂, and Z² is —O—, or —S— (e.g., —O—).

In certain embodiments, Z² is —O—, or —S— (e.g., —O—), and Z³ is C₂₋₃alkylene.

In certain embodiments, Z¹ is CH₂, and Z² is —O—, or —S— (e.g., —O—),and Z³ is C₂₋₃ alkylene.

In certain of the foregoing embodiments when R¹ is —Z¹—Z²—Z³, R¹ is

Variable R²

In some embodiments, R² is:

(i) C₆₋₁₀ aryl, which is optionally further substituted with from 1-4R^(c);

(ii) heteroaryl including from 5-10 ring atoms, wherein from 1-4 ringatoms are heteroatoms, each independently selected from the groupconsisting of N, N(H), N(R^(d)), O, and S, and wherein one or more ofthe heteroaryl ring carbon atoms are optionally substituted with from1-4 independently selected R^(c);

(iii) partially unsaturated C₃₋₁₀ cycloalkyl, which is optionallysubstituted with from 1-4 R^(b); or

(iv) partially unsaturated heterocyclyl including from 3-10 ring atoms,wherein from 1-3 ring atoms are heteroatoms, each independently selectedfrom the group consisting of N, N(H), N(R^(d)), and O, and wherein oneor more of the heterocyclyl ring carbon atoms are optionally substitutedwith from 1-4 independently selected R^(b).

In some embodiments, R² is C₆₋₁₀ aryl, which is optionally substitutedwith from 1-4 R^(c).

In certain embodiments, R² is phenyl, which is optionally substitutedwith from 1-4 R^(c). In certain of the foregoing embodiments, R² can bephenyl, which is optionally substituted with from 1-2 R^(c). As anon-limiting example, R² can be phenyl, which is optionally substitutedwith 2 R^(c).

In certain of the foregoing embodiments when R² is aryl (e.g., phenyl),each occurrence of R^(c) is independently selected from the groupconsisting of:

(i) halo (e.g., F);

(vi) C₁₋₄ haloalkyl (e.g., CF₃);

(vii) C₁₋₄ alkoxy;

(viii) C₁₋₄ haloalkoxy; and

(xiv) —C₁₋₄ thioalkoxy.

As a non-limiting example, each occurrence of R^(c) can be independentlyselected from halo, C₁₋₄ alkoxy, and C₁₋₄ haloalkyl (e.g., eachoccurrence of R^(c) is independently —OCH₃, CF₃, or F).

In certain of the foregoing embodiments when R² is aryl (e.g., phenyl),R² has the following formula (A):

in which each of R², R^(2b), R^(2c), R^(2d), and R^(2e) are eachindependently selected from the group consisting of H and R^(c).

In certain embodiments, four of R^(2a), R^(2b), R^(2c), R^(2d), andR^(2e) are each an independently selected R^(c), and the other is H.

In certain embodiments, three of R^(2a), R^(2b), R^(2c), R^(2d), andR^(2e) are each an independently selected R^(c), and the others are H.

In certain embodiments, two of R^(2a), R^(2b), R^(2c), R^(2d), andR^(2e) are each an independently selected R^(c), and the others are H.In certain of these embodiments, R^(2a) and R^(2e) are each anindependently selected R^(c) (e.g., C₁₋₄ alkoxy; C₁₋₄ haloalkoxy; —C₁₋₄thioalkoxy; C₁₋₄ haloalkyl and halo e.g., each occurrence of R^(c) is anindependently selected C₁₋₄ alkoxy (e.g., —OCH₃). For example, R^(2a)and R^(2c) are each OCH₃.

In certain embodiments, R² is:

In certain of the foregoing embodiments when R² is aryl (e.g., phenyl),R² has formula (B)

In some embodiments, when R² is aryl (e.g., phenyl); and R² has thefollowing formula (A):

from 1-4 of R^(2a), R^(2b), R^(2d), and R^(2e) is an independentlyselected R^(c).

In certain of the foregoing embodiments, each R^(c) is independentlyselected from:

(i) —F;

(ii) cyano;

(iii) C₁₋₃ alkyl, C₅₋₆ alkyl, n-butyl, sec-butyl, iso-butyl;

(iv) C₂₋₆ alkenyl;

(v) C₂₋₆ alkynyl;

(vi) C₁₋₄ haloalkyl;

(vii) C₁₋₄ alkoxy;

(viii) C₁₋₄ haloalkoxy;

(ix) —(C₀₋₃ alkylene)-C₃₋₆ cycloalkyl optionally substituted with from1-4 independently selected C₁₋₄ alkyl;

(x) —S(O)₁₋₂(C₁₋₄ alkyl);

(xii) —OH;

(xiv) —C₁₋₄ thioalkoxy;

(xv) —NO₂;

(xvi) —C(═O)(C₁₋₄ alkyl);

(xvii) —C(═O)O(C₁₋₄ alkyl);

(xviii) —C(═O)OH;

(xix) —C(═O)N(R′)(R″); and

(xx) C₃₋₆ cycloalkoxy.

In some embodiments, R² is heteroaryl including from 5-10 ring atoms,wherein from 1-4 ring atoms are heteroatoms, each independently selectedfrom the group consisting of N, N(H), N(R^(d)), O, and S, and whereinone or more of the heteroaryl ring carbon atoms are optionallysubstituted with from 1-4 independently selected R^(c).

In certain of the foregoing embodiments, R² is heteroaryl including from6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, eachindependently selected from the group consisting of N, N(H), andN(R^(d)), and wherein one or more of the heteroaryl ring carbon atomsare optionally substituted with from 1-4 independently selected R^(c).

As a non-limiting example, R² can be pyridinyl optionally substitutedwith from 1-2 independently selected R^(c).

In certain of the foregoing embodiments when R² is heteroaryl as definedabove (e.g., R² is heteroaryl including from 5-10 ring atoms, whereinfrom 1-4 ring atoms are heteroatoms, each independently selected fromthe group consisting of N, N(H), N(R^(d)), O, and S, and wherein one ormore of the heteroaryl ring carbon atoms are optionally substituted withfrom 1-4 independently selected R^(c)), each R^(c) is independentlyselected from:

(i) halo

(vi) C₁₋₄ haloalkyl (e.g., CF₃);

(vii) C₁₋₄ alkoxy;

(viii) C₁₋₄ haloalkoxy; and

(xiv) —C₁₋₄ thioalkoxy.

As a non-limiting example, each R^(c) can be independently C₁₋₄ alkoxy(e.g., methoxy).

In certain of the foregoing embodiments when R² is heteroaryl, R² is:

or

In certain of the foregoing embodiments when R² is heteroaryl, R² is:

In some embodiments (e.g., when the compound has Formula I-d1), when R²is heteroaryl as defined elsewhere herein, R² is selected from:

(a) heteroaryl including 5 ring atoms, wherein from 1-2 ring atoms areheteroatoms, each independently selected from the group consisting of N,N(H), N(R^(d)), O, and S, and wherein one or more of the heteroaryl ringcarbon atoms are optionally substituted with from 1-4 independentlyselected R^(c);

(b)

wherein each of Q¹, Q², Q³, Q⁴, and Q⁵ is independently selected from N,CH, and CR^(c), provided that:

-   -   from 1-4 of Q¹, Q², Q³, Q⁴, and Q⁵ is independently CR^(c);    -   one or more of Q¹, Q², Q³, Q⁴, and Q⁵ is independently N; and    -   when Q⁵ is CR^(c), one or more of Q¹, Q², Q³, and Q⁴ is CR^(c);        and

(c) heteroaryl including from 9-10 ring atoms, wherein from 1-4 ringatoms are heteroatoms, each independently selected from the groupconsisting of N, N(H), N(R^(d)), O, and S, and wherein one or more ofthe heteroaryl ring carbon atoms are substituted with from 1-4independently selected R^(c),

wherein each occurrence of R^(c) is independently selected from:

(i) —F;

(ii) cyano;

(iii) C₂₋₆ alkyl;

(iv) C₂₋₆ alkenyl;

(v) C₂₋₆ alkynyl;

(vi) C₁₋₄ haloalkyl;

(vii) C₁₋₄ alkoxy;

(viii) C₁₋₄ haloalkoxy;

(ix) —(C₀₋₃ alkylene)-C₃₋₆ cycloalkyl optionally substituted with from1-4 independently selected C₁₋₄ alkyl;

(x) —S(O)₁₋₂(C₁₋₄ alkyl);

(xi) —NR^(c)R^(f);

(xiii) —S(O)₁₋₂(NR′R″);

(xiv) —C₁₋₄ thioalkoxy;

(xv) —NO₂;

(xvi) —C(═O)(C₁₋₄ alkyl);

(xvii) —C(═O)O(C₁₋₄ alkyl);

(xviii) —C(═O)OH;

(xix) —C(═O)N(R′)(R″); and

(xx) C₃₋₆ cycloalkoxy.

Variable R³

In some embodiments, one or more occurrences of R³ is each independentlyselected from R^(c′) and -L⁴-R⁴.

In some embodiments, one occurrence of R³ is -L⁴-R⁴.

In certain of the foregoing embodiments when one occurrence R³ is-L⁴-R⁴, each of the remaining occurrences of R³ is independentlyselected from the group consisting of H and R^(c′) (e.g., R^(c′) can behalo, e.g., Br or Cl; or R^(c′) can be —OH or NH₂). For example, each ofthe remaining occurrences of R³ can be H.

In some embodiments, one occurrence of R³ is -L⁴-R⁴, and one occurrenceof R³ is H or R^(c′) (e.g., R^(c′) can be halo, e.g., Br or Cl; orR^(c′) can be NH₂).

In some embodiments, one occurrence of R³ is -L⁴-R⁴, and one occurrenceof R³ is R^(c′) (e.g., R^(c′) can be halo, e.g., Br or Cl (e.g., R^(c′)can be Cl)).

In some embodiments, one occurrence of R³ is -L⁴-R⁴, and one occurrenceof R³ is H.

In some embodiments, two occurrences of R³ are independently selected-L⁴-R⁴.

In certain of the foregoing embodiments, any remaining occurrence of R³is selected from the group consisting of H and R^(c′). For example, anyremaining occurrence of R³ can be H.

As a non-limiting example of the foregoing embodiments, each of X² andX³ can be CR³, wherein each R^(a) is an independently selected -L⁴-R⁴(in certain embodiments, each of X¹ and X⁴ is independently CH or N).

In some embodiments, one occurrence of R³ is H or R^(c′) (e.g., R^(c′)can be halo, e.g., Br or Cl; or R^(c′) can be —OH or NH₂).

In certain embodiments, when one occurrence of R³ is R^(c′), each of theremaining occurrences of R³ is independently H or R^(c′). For example,each of the remaining occurrences of R³ can be H.

In certain embodiments, when one occurrence of R³ is R^(c′); and one ormore occurrences of the remaining R³ is independently selected from-L⁴-R⁴ and R^(c′).

In some embodiments, one occurrence of R⁶ is H.

Non-Limiting Combinations of X¹-X⁴ and R³

In some embodiments, the moiety

(the originally provided structure in U.S. Provisional Application Ser.No. 62/742,218

has been redrawn to further clarify points of connection) is

(the originally provided structure

in U.S. Provisional Application Ser. No. 62/742,218 has been redrawn tofurther clarify points of connection), wherein * denotes point ofattachment to NR²; and

denotes point of attachment to A¹.

In certain embodiments, R^(3B) is -L⁴-R⁴; and R^(3C) is H (e.g., -L⁴ canbe NHS(O)₂).

In certain embodiments, R^(3B) is -L⁴-R⁴; and R^(3C) is R^(c′) (e.g.,R^(c′) can be halo such as —Cl; and/or -L⁴ can be NHS(O)₂).

In certain embodiments, R^(3B) is -L⁴-R⁴; and R^(3C) is an independentlyselected -L⁴-R⁴. In certain of the foregoing embodiments, the -L⁴ ofR^(3B) is different from the -L⁴ of R^(3C). As a non-limiting example,the -L⁴ of R^(3B) can be NHS(O)₂; and the -L⁴ of R^(3C) can be a bond.

In certain embodiments, R^(3B) is H; and R^(3C) is -L⁴-R⁴ (e.g., -L⁴ canbe NHS(O)₂).

In certain embodiments, R^(3B) is R^(c′); and R^(3C) is -L⁴-R⁴ (e.g.,-L⁴ can be NHS(O)₂).

In certain embodiments, R³ is H; and R^(3C) is R^(c′).

In some embodiments, the moiety

the originally provided structure

in U.S. Provisional Application Ser. No. 62/742,218 has been redrawn tofurther clarify points of connection) is

(the originally provided structure

in U.S. Provisional Application Ser. No. 62/742,218 has been redrawn tofurther clarify points of connection), wherein * denotes point ofattachment to NR²; and

denotes point of attachment to A¹.

In certain embodiments, R^(3A) is H.

In certain of the foregoing embodiments, R^(3B) is -L⁴-R⁴ (e.g., -L⁴ canbe NHS(O)₂).

In some embodiments, the moiety

(the originally provided structure

in U.S. Provisional Application Ser. No. 62/742,218 has been redrawn tofurther clarify points of connection)

is (the originally provided structure

in U.S. Provisional Application Ser. No. 62/742,218 has been redrawn tofurther clarify points of connection), wherein * denotes point ofattachment to NR²; and

denotes point of attachment to A¹.

In certain of the foregoing embodiments, R^(3B) is -L⁴-R⁴ (e.g., -L⁴ canbe NHS(O)₂).

In certain of the foregoing embodiments, R^(3B) is -L⁴-R⁴ (e.g., -L⁴ canbe NHS(O)₂); and R^(3C) is H.

In certain of the foregoing embodiments, R^(3B) is -L⁴-R⁴ (e.g., -L⁴ canbe NHS(O)₂); and R^(3C) is R^(c′).

In certain of the foregoing embodiments, R^(3B) is -L⁴-R⁴ (e.g., -L⁴ canbe NHS(O)₂); and R^(3C) is an independently selected -L⁴-R⁴. In certainof the foregoing embodiments, the -L⁴ of R^(3B) is different from the-L⁴ of R^(3C). As a non-limiting example, the -L⁴ of R^(3B) can beNHS(O)₂; and the -L⁴ of R^(3C) can be a bond.

In some embodiments, the moiety

(the originally provided structure

in U.S. Provisional Application Ser. No. 62/742,218 has been redrawn tofurther clarify points of connection) is

(the originally provided structure

in U.S. Provisional Application Ser. No. 62/742,218 has been redrawn tofurther clarify points of connection), wherein * denotes point ofattachment to NR²; and

denotes point of attachment to A¹.

In certain embodiments, R^(3D) is H.

In certain of the foregoing embodiments, R^(3B) is -L⁴-R⁴ (e.g., -L⁴ canbe NHS(O)₂).

In certain of the foregoing embodiments, R^(3B) is -L⁴-R⁴ (e.g., -L⁴ canbe NHS(O)₂); and R^(3C) is H.

In certain of the foregoing embodiments, R^(3B) is -L⁴-R⁴ (e.g., -L⁴ canbe NHS(O)₂); and R^(3C) is R^(c′).

In certain of the foregoing embodiments, R^(3B) is -L⁴-R⁴ (e.g., -L⁴ canbe NHS(O)₂); and R^(3C) is an independently selected -L⁴-R⁴. In certainof the foregoing embodiments, the -L⁴ of R^(3B) is different from the-L⁴ of R^(c). As a non-limiting example, the -L⁴ of R^(3B) can beNHS(O)₂; and the -L⁴ of R^(3C) can be a bond.

Variable L⁴

In some embodiments, -L⁴ is —N(H)S(O)₁₋₂— or —N(R^(d))S(O)₁₋₂. (e.g.,N(C₁₋₃ alkyl)S(O)₂).

In certain of the foregoing embodiments, -L⁴ is —N(H)S(O)₂—.

In some embodiments, -L⁴ is —N(H)S(O)(═NH)—, —N(R^(d))S(O)(═NH),N(H)S(O)(═NR^(d))—, or —N(R^(d))S(O)(═NR^(d))—.

In certain of the foregoing embodiments, -L⁴ is —N(H)S(O)(═NH)—.

In some embodiments, -L⁴ is —S(O)(═NH)NH—, —S(O)(═NR^(d))NH—,—S(O)(═NH)NR^(d)—, or —S(O)(═NR^(d))NR^(d)—.

In certain of the foregoing embodiments, -L⁴ is —S(O)(═NH)NH—.

In some embodiments, -L⁴ is —S(O)₁₋₂N(H)— or —S(O)₁₋₂N(R^(d))—.

In certain of the foregoing embodiments, -L⁴ is —S(O)₂N(H)—.

In some embodiments, -L⁴ is —N(H)C(O)— or —N(R^(d))C(O).

In certain of the foregoing embodiments, -L⁴ is —N(H)C(O)—.

In some embodiments, L⁴ is —C(O)NH— or —C(O)N(R^(d))—.

In some embodiments, -L⁴ is —N(H)—, —N(R^(d))—, or —N(R⁴)—.

In certain embodiments, -L⁴ is —N(H)— or —N(R⁴)—.

In some embodiments, -L⁴ is a single bond.

In some embodiments, -L⁴ is C≡C.

In some embodiments, -L⁴ is —O—.

In some embodiments, L⁴ is selected from the group consisting of:—N(H)S(O)₁₋₂N(H)—, —N(R^(d))S(O)₁₋₂N(H)—, —N(H)S(O)₁₋₂N(R^(d))—, and—N(R^(d))S(O)₁₋₂N(R^(d))—.

In some embodiments, L⁴ is —N(H)S(O)₁₋₂N(H)— (e.g., —N(H)S(O)₂N(H)—).

In some embodiments, L⁴ is —N(H)S(O)₁₋₂N(R^(d))— (e.g.,—N(H)S(O)₂N(R^(d))—, e.g., —N(H)S(O)₂N(C₁₋₃ alkyl)-).

In some embodiments, -L⁴ is selected from the group consisting of—N(H)S(O)₂—, C≡C, a single bond, —C(O)N(H)—, —N(H)—, —N(R⁴)—,—N(R^(d))—, and —N(H)C(O)—.

In certain of the foregoing embodiments, -L⁴ is selected from the groupconsisting of —N(H)S(O)₂—, a single bond, —NH—, —N(R⁴)—, and —N(H)C(O)—.

In some embodiments, -L⁴ is selected from:

-   -   (i) a bond (in certain embodiments, when -L⁴ is a bond; and R⁴        is —(Y³)_(p)—Y⁴, then p is 1).    -   (ii) N(R⁴);    -   (iii) —N(H)S(O)₁₋₂— or —N(R^(d))S(O)₁₋₂—;    -   (iv) —S(O)₁₋₂N(H)— or —S(O)₁₋₂N(R^(d))—.    -   (vi) —S(O)₁₋₂—;    -   (viii) —N(H)C(O)— or —N(R^(d))C(O)—;    -   (ix) —C≡C;    -   (x) —N(H)S(O)(═NH)—, —N(R^(d))S(O)(═NH), —N(H)S(O)(═NR^(d))—, or        —N(R^(d))S(O)(═NR^(d))—    -   (xi) —S(O)(═NH)NH—, —S(O)(═NR^(d))NH—, —S(O)(═NH)NR^(d)—, or        —S(O)(═NR^(d))NR^(d)—; and    -   (xii) —S(O)(═NH)— or —S(O)(═NR^(d)).

Variable R⁴

In some embodiments, R⁴ is —(Y³)_(p)—Y⁴.

In some embodiments, p is 0.

In other embodiments, p is 1. In certain of these embodiments, Y³ isC₁₋₃ alkylene. For example, Y³ can be CH₂ or CH₂—CH₂.

In some embodiments, Y⁴ is C₆₋₁₀ aryl, which is optionally substitutedwith from 1-4 R^(c).

In some embodiments, Y⁴ is phenyl, which is optionally substituted withfrom 1-2 (e.g., 1) R^(c).

In certain embodiments when Y⁴ is C₆₋₁₀ aryl, which is optionallysubstituted with from 1-4 R^(c) (e.g., when Y⁴ is phenyl, which isoptionally substituted with from 1-2 (e.g., 1) R^(c)), each occurrenceof R^(c) is independently selected from the group consisting of:

(i) halo;

(ii) cyano;

(iii) C₁₋₆ alkyl;

(iv) C₂₋₆ alkenyl;

(v) C₂₋₆ alkynyl;

(vi) C₁₋₄ haloalkyl;

(vii) C₁₋₄ alkoxy;

(viii) C₁₋₄ haloalkoxy;

(ix) —(C₀₋₃ alkylene)-C₃₋₆ cycloalkyl optionally substituted with from1-4 independently selected C₁₋₄ alkyl;

(xiv) —C₁₋₄ thioalkoxy, and

(xx) C₃₋₆ cycloalkoxy.

In certain embodiments when Y⁴ is C₆₋₁₀ aryl, which is optionallysubstituted with from 1-4 R^(c) (e.g., when Y⁴ is phenyl, which isoptionally substituted with from 1-2 (e.g., 1) R^(c)), each occurrenceof R^(c) is independently selected from the group consisting of:

(i) halo;

(iii) C₁₋₆ alkyl;

(vi) C₁₋₄ haloalkyl;

(vii) C₁₋₄ alkoxy; and

(viii) C₁₋₄ haloalkoxy.

In certain embodiments when Y⁴ is C₆₋₁₀ aryl, each occurrence of R^(c)is independently selected from the group consisting of:

(vii) C₁₋₄ alkoxy;

(viii) C₁₋₄ haloalkoxy; and

(xiv) —C₁₋₄ thioalkoxy.

In certain embodiments, Y⁴ is C₆₋₁₀ aryl (e.g., phenyl), which isunsubstituted.

In certain embodiments when p=1 and Y⁴ is C₆₋₁₀ aryl, R⁴ is selectedfrom the group consisting of:

In certain embodiments when p=1 and Y⁴ is C₆₋₁₀ aryl, R⁴ is selectedfrom the group consisting of:

In certain embodiments when p=0 and Y⁴ is C₆₋₁₀ aryl, R⁴ is:

In certain embodiments when p=0 and Y⁴ is C₆₋₁₀ aryl, R⁴ is:

In some embodiments, Y⁴ is C₃₋₆ (e.g., C₃₋₆ or C₆) cycloalkyl, which isoptionally substituted with from 1-4 R^(b).

In certain of the foregoing embodiments, Y⁴ is cyclopropyl, which isoptionally substituted with from 1-2 R^(b). For example, Y⁴ isunsubstituted cyclopropyl.

In some embodiments, Y⁴ is C₆ cycloalkyl (e.g., cyclohexyl), which isoptionally substituted with from 1-2 R^(b).

In certain of the foregoing embodiments when Y⁴ is cycloalkyl which isoptionally substituted with from 1-4 R^(b), each occurrence of R^(b) isindependently selected from the group consisting of: —F, C₁₋₆ alkyl,C₁₋₄ haloalkyl, and —OH (e.g., R^(b) can be OH; and/or R^(b) can be C₁₋₆alkyl such as methyl).

In certain embodiments when p=1 and Y⁴ is C₃₋₆ cycloalkyl optionallysubstituted with from 1-4 R^(b), R⁴ is selected from the groupconsisting of:

In certain embodiments when p=1 and Y⁴ is C₃₋₆ cycloalkyl optionallysubstituted with from 1-4 R^(b), R⁴ is selected from the groupconsisting of:

In certain embodiments when p=O and Y⁴ is C₃₋₆ cycloalkyl optionallysubstituted with from 1-4 R^(b), R⁴ is selected from the groupconsisting of:

In certain embodiments, Y⁴ is C₃₋₆ (e.g., C₃₋₄ or C₆) cycloalkyl, whichis unsubstituted.

In certain of these embodiments, Y⁴ is unsubstituted cyclopropyl orunsubstituted cyclobutyl (e.g., unsubstituted cyclopropyl).

In some embodiments, Y⁴ is heteroaryl including from 5-10 ring atoms,wherein from 1-4 ring atoms are heteroatoms, each independently selectedfrom the group consisting of N, N(H), N(R^(d)), O, and S, and whereinone or more of the heteroaryl ring carbon atoms are optionallysubstituted with from 1-4 independently selected R^(c).

In certain of the foregoing embodiments, Y⁴ is heteroaryl including 6ring atoms, wherein from 1-4 ring atoms are heteroatoms, eachindependently selected from the group consisting of N, N(H), andN(R^(d)), and wherein one or more of the heteroaryl ring carbon atomsare optionally substituted with from 1-4 independently selected R^(c).

As non-limiting examples of the foregoing, Y⁴ can be pyridinyl (e.g.,2-pyridinyl, 3-pyridinyl, or 4-pyridinyl), pyrimidinyl (e.g.,2-pyrimidinyl or 5-pyrimidinyl), or pyrazinyl, each of which isoptionally substituted with from 1-2 independently selected R^(c).

For example Y⁴ can be pyridinyl, pyrimidinyl, or pyrazinyl, each ofwhich is unsubstituted.

In certain embodiments when Y⁴ is heteroaryl optionally substituted withone or more independently selected R^(c) as defined supra, eachoccurrence of R^(c) is independently selected from the group consistingof:

-   -   (i) halo;    -   (ii) cyano;    -   (iii) C₁₋₆ alkyl;    -   (iv) C₂₋₆ alkenyl;    -   (v) C₂₋₆ alkynyl;    -   (vi) C₁₋₄ haloalkyl;    -   (vii) C₁₋₄ alkoxy;    -   (viii) C₁₋₄ haloalkoxy;    -   (ix) —(C₀₋₃ alkylene)-C₃₋₆ cycloalkyl optionally substituted        with from 1-4 independently selected C₁₋₄ alkyl;    -   (xii) OH;    -   (xiv) —C₁₋₄ thioalkoxy, and    -   (xx) C₃₋₆ cycloalkoxy.

In certain of these embodiments, each occurrence of R^(c) isindependently selected from the group consisting of:

(i) halo (e.g., F, Cl);

(iii) C₁₋₆ alkyl (e.g., methyl); and

(xii) OH.

In certain embodiments when p=1; and Y⁴ is heteroaryl, R⁴ is selectedfrom the group consisting of:

In certain embodiments when p=1; and Y⁴ is heteroaryl, R⁴ is selectedfrom the group consisting of:

In certain embodiments when p=0; and Y⁴ is heteroaryl, R⁴ is selectedfrom the group consisting of:

In certain embodiments when p=0; and Y⁴ is heteroaryl, R⁴ is selectedfrom the group consisting of:

In some embodiments, Y⁴ is heterocyclyl including from 3-10 ring atoms,wherein from 1-3 ring atoms are heteroatoms, each independently selectedfrom the group consisting of N, N(H), N(R^(d)), and O, and wherein oneor more of the heterocyclyl ring carbon atoms are optionally substitutedwith from 1-4 independently selected R^(b).

In certain of the foregoing embodiments, Y⁴ is heterocyclyl includingfrom 4-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, eachindependently selected from the group consisting of N, N(H), N(R^(d)),and O, and wherein one or more of the heterocyclyl ring carbon atoms areoptionally substituted with from 1-4 independently selected R^(b).

In certain embodiments, Y⁴ heterocyclyl including from 4 ring atoms,wherein 1 ring atom is a heteroatom, independently selected from thegroup consisting of N, N(H), N(R^(d)), and O, and wherein one or more ofthe heterocyclyl ring carbon atoms are optionally substituted with from1-2 independently selected R^(b).

As a non-limiting example, Y⁴ can be oxetanyl optionally substitutedwith from 1-2 independently selected R^(b) (e.g., unsubstitutedoxetanyl).

As another non-limiting example, Y⁴ can be azetidinyl optionallysubstituted with from 1-2 independently selected R^(b) (e.g., azetidinylsubstituted with one R^(b)).

In some embodiments, Y⁴ is heterocyclyl including from 6 ring atoms,wherein from 1-2 ring atoms are heteroatoms, each independently selectedfrom the group consisting of N, N(H), N(R^(d)), and O, and wherein oneor more of the heterocyclyl ring carbon atoms are optionally substitutedwith from 1-4 independently selected R^(b).

As non-limiting examples, Y⁴ can be selected from the group consistingof tetrahydropyranyl, piperidinyl, piperazinyl, and morpholinyl, each ofwhich is optionally substituted with from 1-2 independently selectedR^(b).

As non-limiting examples, Y⁴ can be selected from tetrahydropyranyl,piperidinyl, and morpholinyl, each of which is optionally substitutedwith from 1-2 independently selected R^(b).

In certain of the foregoing embodiments when Y⁴ is heterocyclyloptionally substituted with from 1-4 independently selected R^(b), eachoccurrence of R^(b) is independently selected from the group consistingof: —F, C₁₋₆ alkyl, C₁₋₄ haloalkyl, oxo, and —OH.

In certain of the foregoing embodiments when Y⁴ is heterocyclyloptionally substituted with from 1-4 independently selected R^(b), eachoccurrence of R^(b) is independently selected from the group consistingof: —F, C₁₋₆ alkyl, C₁₋₄ haloalkyl, and —OH (e.g., R^(b) can be OH).

In certain embodiments when p=1; and Y⁴ is heterocyclyl optionallysubstituted with from 1-4 independently selected R^(b), R⁴ is selectedfrom the group consisting of:

In certain embodiments when p=1; and Y⁴ is heterocyclyl optionallysubstituted with from 1-4 independently selected R^(b), R⁴ is

In certain embodiments when p=0; and Y⁴ is heterocyclyl optionallysubstituted with from 1-4 independently selected R^(b), R⁴ is selectedfrom the group consisting of:

In certain embodiments when p=0; and Y⁴ is heterocyclyl optionallysubstituted with from 1-4 independently selected R^(b), R⁴ is selectedfrom the group consisting of:

In some embodiments, R⁴ is C₁₋₁₀ alkyl, optionally substituted with from1-6 independently selected R^(a).

In certain embodiments, R⁴ is C₁₋₆ alkyl, optionally substituted withfrom 1-6 independently selected R^(a).

In certain embodiments, R⁴ is C₁₋₆ alkyl, optionally substituted withfrom 1-2 independently selected R^(a). For example, R⁴ can be methyl.

In certain of the foregoing embodiments when R⁴ is C₁₋₆alkyl, eachoccurrence of R^(a) is independently selected from the group consistingof: —F, —OH; C₁₋₄ alkoxy; and C₁₋₄ haloalkoxy.

In certain embodiments, each occurrence of R^(a) is independently —OH.For example, R⁴ is

In some embodiments, R⁴ is selected from the group consisting of methyl,ethyl,

In some embodiments, R⁴ is selected from methyl and

In some embodiments, R⁴ is C₂₋₁₀ (e.g., C₂₋₄) alkynyl, which isoptionally substituted with from 1-6 (e.g., from 1-3) independentlyselected R^(a) (e.g., unsubstituted C₂₋₄ alkynyl such as

In some embodiments, R⁴ is C₂₋₁₀ (e.g., C₂₋₄) alkenyl, which isoptionally substituted with from 1-6 (e.g., from 1-3) independentlyselected R^(a) (e.g., unsubstituted C₂₋₄ alkenyl such as vinyl).

In some embodiments (e.g., when -L⁴ is a bond or —O—), R⁴ is C₂₋₁₀alkyl, optionally substituted with from 1-6 independently selectedR^(a); or methyl optionally substituted with from 1-2 independentlyselected R^(a).

In certain embodiments (e.g., when -L⁴ is a bond or —O—), R⁴ is C₂₋₁₀alkyl, optionally substituted with from 1-6 independently selectedR^(a); or methyl substituted with from 1-2 independently selected R^(a).

Non-Limiting Combinations of -L⁴ and R⁴

Non-Limiting Combination [A]

In some embodiments, -L⁴ is selected from the group consisting of—N(H)S(O)₂—, —N(H)S(O)₂N(H)—, —N(H)S(O)₂N(R^(d))—, C≡C, a single bond,—C(O)N(H)—, —N(H)—, —N(R⁴)—, —N(R^(d))—, and —N(H)C(O)—; and

R⁴ is selected from the group consisting of:

(i) C₁₋₆ alkyl optionally substituted with 1-2 R^(a);

(ii) —(Y³)_(p)—Y⁴; and

(iii) C₂₋₁₀ alkenyl or C₂₋₁₀ alkynyl, each of which is optionallysubstituted with from 1-3 independently selected R^(a).

In certain embodiments, -L⁴ is selected from the group consisting of—N(H)S(O)₂—, —N(H)S(O)₂N(H)—, and —N(H)S(O)₂N(R^(d))—; and

R⁴ is selected from the group consisting of:

(i) C₁₋₆ alkyl optionally substituted with 1-2 R^(a);

(ii) —(Y³)_(p)—Y⁴; and

(iii) C₂₋₁₀ alkenyl or C₂₋₁₀ alkynyl, each of which is optionallysubstituted with from 1-3 independently selected R^(a).

In some embodiments, -L⁴ is selected from the group consisting of—N(H)S(O)₂—, C≡C, a single bond, —C(O)N(H)—, —N(H)—, —N(R⁴)—,—N(R^(d))—, and —N(H)C(O)—; and

R⁴ is selected from the group consisting of:

(i) C₁₋₆ alkyl optionally substituted with 1-2 R^(a); and

(ii) —(Y³)_(p)—Y⁴.

In certain embodiments, -L⁴ is selected from the group consisting of—N(H)S(O)₂—, a single bond, —NH—, —N(R⁴)—, and —N(H)C(O)—; and

R⁴ is selected from the group consisting of:

(i) C₁₋₆ alkyl optionally substituted with 1-2 R^(a); and

(ii) —(Y³)_(p)—Y⁴.

In certain embodiments, -L⁴ is —N(H)S(O)₂—; and R⁴ is selected from thegroup consisting of:

(i) C₁₋₆ alkyl optionally substituted with 1-2 R^(a); and

(ii) —(Y³)_(p)—Y⁴.

In certain embodiments, -L⁴ is a single bond; and R⁴ is selected fromthe group consisting of:

(i) C₁₋₆ alkyl optionally substituted with 1-2 R^(a); and

(ii) —(Y³)_(p)—Y⁴.

In certain embodiments, -L⁴ is —NH— or —N(R⁴)—; and R⁴ is selected fromthe group consisting of:

(i) C₁₋₆ alkyl optionally substituted with 1-2 R^(a); and

(ii) —(Y³)_(p)—Y⁴.

In certain embodiments, -L⁴ is —N(H)C(O)—; and R⁴ is selected from thegroup consisting of:

(i) C₁₋₆ alkyl optionally substituted with 1-2 R^(a); and

(ii) —(Y³)_(p)—Y⁴.

In certain of these embodiments, -L⁴ is —N(H)S(O)₂N(H)— or—N(H)S(O)₂N(R^(d))—; and

R⁴ is selected from the group consisting of:

(i) C₁₋₆ alkyl optionally substituted with 1-2 R^(a); and

(ii) —(Y³)_(p)—Y⁴.

In certain embodiments, -L⁴ is —N(H)S(O)₂—; and R⁴ is selected from thegroup consisting of:

R⁴ is selected from the group consisting of:

(i) C₁₋₆ alkyl optionally substituted with 1-2 R^(a);

(ii) —(Y³)_(p)—Y⁴; and

(iii) C₂₋₁₀ alkenyl or C₂₋₁₀ alkynyl, each of which is optionallysubstituted with from 1-3 independently selected R^(a).

In certain embodiments, -L⁴ is a single bond; and R⁴ is selected fromthe group consisting of:

R⁴ is selected from the group consisting of:

(i) C₁₋₆ alkyl optionally substituted with 1-2 R^(a);

(ii) —(Y³)_(p)—Y⁴; and

(iii) C₂₋₁₀ alkenyl or C₂₋₁₀ alkynyl, each of which is optionallysubstituted with from 1-3 independently selected R^(a).

In certain embodiments, -L⁴ is —NH— or —N(R⁴)—; and R⁴ is selected fromthe group consisting of:

R⁴ is selected from the group consisting of:

(i) C₁₋₆ alkyl optionally substituted with 1-2 R^(a);

(ii) —(Y³)_(p)—Y⁴; and

(iii) C₂₋₁₀ alkenyl or C₂₋₁₀ alkynyl, each of which is optionallysubstituted with from 1-3 independently selected R^(a).

In certain embodiments, -L⁴ is —N(H)C(O)—; and R⁴ is selected from thegroup consisting of:

R⁴ is selected from the group consisting of:

(i) C₁₋₆ alkyl optionally substituted with 1-2 R^(a);

(ii) —(Y³)_(p)—Y⁴; and

(iii) C₂₋₁₀ alkenyl or C₂₋₁₀ alkynyl, each of which is optionallysubstituted with from 1-3 independently selected R^(a).

In certain embodiments, -L⁴ is —N(H)S(O)₂N(H)— or —N(H)S(O)₂N(R^(d))—;and

R⁴ is selected from the group consisting of:

(i) C₁₋₆ alkyl optionally substituted with 1-2 R^(a);

(ii) —(Y³)_(p)—Y⁴; and

(iii) C₂₋₁₀ alkenyl or C₂₋₁₀ alkynyl, each of which is optionallysubstituted with from 1-3 independently selected R^(a).

In some embodiments of [A], R⁴ is C₁₋₆ alkyl optionally substituted with1-2 R^(a).

In some embodiments of [A], R⁴ is C₂₋₁₀ alkenyl or C₂₋₁₀ alkynyl, eachof which is optionally substituted with from 1-3 independently selectedR^(a).

In certain of these embodiments, R⁴ is C₂₋₁₀ (e.g., C₂₋₅) alkynyl, whichis optionally substituted with from 1-3 independently selected R^(a)(e.g., unsubstituted C₂₋₅ alkynyl such as

In some embodiments of [A], R⁴ is —(Y³)_(p)—Y⁴. In certain embodiments,Y⁴ is C₆₋₁₀ aryl, which is optionally substituted with from 1-4 R^(c).For example, Y⁴ can be phenyl which is optionally substituted with from1-2 (e.g., 1) R^(c).

In some embodiments of [A] when R⁴ is —(Y³)_(p)—Y⁴, Y⁴ is is C₃₋₆ (e.g.,C₃₋₆ or C₆) cycloalkyl, which is optionally substituted with from 1-4R^(b). In certain embodiments, Y⁴ is C₃₋₄ cycloalkyl or C₆ cycloalkyl,each of which is optionally substituted with from 1-2 R^(b) (e.g., R^(b)can be —OH).

In some embodiments of [A], R⁴ is —(Y³)_(p)—Y⁴. In certain embodiments,Y⁴ is heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ringatoms are heteroatoms, each independently selected from the groupconsisting of N, N(H), N(R^(d)), and O, and wherein one or more of theheterocyclyl ring carbon atoms are optionally substituted with from 1-2independently selected R^(b). In certain embodiments, Y⁴ is heterocyclylincluding 6 ring atoms, wherein from 1-3 ring atoms are heteroatoms,each independently selected from the group consisting of N, N(H),N(R^(d)), and O, and wherein one or more of the heterocyclyl ring carbonatoms are optionally substituted with from 1-2 independently selectedR^(b) (e.g., Y⁴ can be tetrahydropyranyl, piperidinyl, or morpholinyl,each of which is optionally substituted with from 1-2 independentlyselected R^(b)). In certain embodiments, Y⁴ is heterocyclyl including 4ring atoms, wherein from 1-3 ring atoms are heteroatoms, eachindependently selected from the group consisting of N, N(H), N(R^(d)),and O, and wherein one or more of the heterocyclyl ring carbon atoms areoptionally substituted with from 1-2 independently selected R^(b)(e.g.,Y⁴ can be oxetanyl; or Y⁴ can be azetidinyl).

In some embodiments of [A], R⁴ is —(Y³)_(p)—Y⁴. In certain embodiments,Y⁴ is heteroaryl including 6 ring atoms, wherein from 1-4 ring atoms areheteroatoms, each independently selected from the group consisting of N,N(H), and N(R^(d)), and wherein one or more of the heteroaryl ringcarbon atoms are optionally substituted with from 1-4 independentlyselected R^(c). In certain embodiments, Y⁴ is pyridinyl (e.g.,2-pyridinyl, 3-pyridinyl, or 4-pyridinyl), pyrimidinyl (e.g.,2-pyrimidinyl or 5-pyrimidinyl), or pyrazinyl, each of which isoptionally substituted with from 1-2 independently selected R^(c).

In certain of the foregoing embodiments of [A] when R⁴ is —(Y³)_(p)—Y⁴,p=0.

In other embodiments of [A] when R⁴ is —(Y³)_(p)—Y⁴, p=1. In certain ofthese embodiments, V is C₁₋₃ alkylene (e.g., CH₂, CH₂—CH₂).

In some embodiments when R³ is -L⁴-R⁴, R³ is selected from the groupconsisting of:

In some embodiments when R³ is -L⁴-R⁴, R³ is selected from the groupconsisting of:

In some embodiments when R³ is -L⁴-R⁴, R³ is selected from the groupconsisting of:

In some embodiments when R³ is -L⁴-R⁴, R³ is selected from the groupconsisting of:

In some embodiments when R³ is -L⁴-R⁴, R³ is selected from the groupconsisting of:

In some embodiments when R³ is -L⁴-R⁴, R³ is selected from the groupconsisting of:

In some embodiments when R³ is -L⁴-R⁴, R³ is selected from the groupconsisting of:

In some embodiments when R³ is -L⁴-R⁴, R³ is selected from the groupconsisting of:

In some embodiments when R³ is -L⁴-R⁴, R³ is selected from the groupconsisting of:

In some embodiments when R³ is -L⁴-R⁴, R³ is selected from the groupconsisting of:

In some embodiments when R³ is -L⁴-R⁴, R³ is selected from the groupconsisting of:

In some embodiments when R³ is -L⁴-R⁴, R³ is selected from the groupconsisting of:

In some embodiments when R³ is -L⁴-R⁴, R³ is selected from the groupconsisting of:

In some embodiments when R³ is -L⁴-R⁴, R³ is selected from the groupconsisting of:

In some embodiments when R³ is -L⁴-R⁴, R³ is selected from the groupconsisting of:

NHMe, and NMe₂.

In some embodiments when R³ is -L⁴-R⁴, R³ is selected from the groupconsisting of:

In some embodiments when R³ is -L⁴-R⁴, R³ is selected from the groupconsisting of:

In certain of the foregoing embodiments, R³ is

Variable R^(c′)

In some embodiments, each occurrence of R^(c′) is independently selectedfrom the group consisting of:

(i) halo (e.g., —F, Cl);

(ii) cyano;

(iii) —OH;

(iv) —NO₂;

(v) —C(═O)(C₁₋₄ alkyl);

(vi) —C(═O)O(C₁₋₄ alkyl);

(vii) —C(═O)OH; and

(viii) —NH₂.

In certain embodiments, each occurrence of R^(c′) is independentlyselected from the group consisting of:

(i) halo (e.g., —F, Cl);

(iii) —OH;

(iv) —NO₂;

(v) —C(═O)(C₁₋₄ alkyl); and

(vi) —C(═O)O(C₁₋₄ alkyl).

In certain embodiments, each occurrence of R^(c′) is independentlyselected from halo (e.g., —F, Cl).

In certain embodiments, each occurrence of R^(c′) is independentlyselected from OH and NH₂.

Non-Limiting Combinations

Non-Limiting Combinations [1]

In some embodiments:

R¹ is —(Y¹)_(n)—Y²; and

R² is C₆₋₁₀ aryl, which is optionally substituted with from 1-4 R^(c).

In certain of these embodiments, n is 0.

In certain of the foregoing embodiments of [1], from 1-2 of X¹, X², X³,and X⁴ are N; and from 2-3 of X¹, X², X³, and X⁴ are each anindependently selected CR³.

In certain of the foregoing embodiments of [1], one of X¹, X², X³, andX⁴ is N; and each of the remaining X¹, X², X³, and X⁴ is anindependently selected CR³; or

two of X, X², X³, and X⁴ are N; and each of the remaining X¹, X², X³,and X⁴ is an independently selected CR³.

In certain embodiments, from 1-2 of X² and X³ is independently CR³, suchas wherein both of X² and X³ are each an independently selected CR³. Incertain of the foregoing embodiments, each of X¹ and X⁴ is independentlyCH or N (e.g., each of X¹ and X⁴ is N).

In certain of the foregoing embodiments of [1], one occurrence of R³ is-L⁴-R⁴.

In certain of the foregoing embodiments of [1], R⁴ is —(Y³)_(p)—Y⁴.

In certain of the foregoing embodiments when R⁴ is (Y³)_(p)—Y⁴, p=1. Inother embodiments, p=0.

In certain of the foregoing embodiments of [1], R⁴ is C₁₋₁₀ alkyloptionally substituted with from 1-6 independently selected R^(a).

In certain of the foregoing embodiments of [1], each of the remainingoccurrences of R³ is independently selected from the group consisting ofH and R^(c′). For example, each of the remaining occurrences of R³ canbe independently H.

In certain of the foregoing embodiments of [1], when one occurrence ofR³ is -L⁴-R⁴, one occurrence of R^(a) is H.

In certain of the foregoing embodiments of [1], when one occurrence ofR³ is -L⁴-R⁴, one occurrence of R^(a) is R^(c′) (e.g., halo (e.g., Br orCl, e.g., Cl)).

In some embodiments of [1], one occurrence of R³ is R^(c′) (e.g., Br orCl, e.g., Cl); and each of the remaining occurrences of R³ is H.

In some embodiments of [1], Y² is as defined in any one of claims 14-20and 26-28; and each R^(c), when present, is independently as defined inany one of claims 21-24.

In some embodiments of [1], Y² is as defined in any one of claims 14-18;and each R^(c), when present, is as defined in any one of claims 21-23.

In some embodiments of [1], Y² is as defined in any one of claims 16-18;and each R^(c), when present, is as defined in any one of claims 21-23.

In some embodiments of [1], Y² is as defined in claim 18; and eachR^(c), when present, is as defined in claim 23.

In certain embodiments of [1], R¹ is R¹ is

such as

In some embodiments of [1], R¹ is as defined in any one of claims 10-23of U.S. 62/742,218, filed Oct. 5, 2018. In certain of the foregoingembodiments, R¹ is as defined in any one of claims 16-23 U.S.62/742,218, filed Oct. 5, 2018. For example, R¹ can be as defined inclaim 23 U.S. 62/742,218, filed Oct. 5, 2018. In some embodiments of[1], R² is C₆₋₁₀ aryl, which is optionally substituted with from 1-4R^(c), such as phenyl, which is optionally substituted with from 1-4R^(c) or 1-2 R^(c) or 2 R^(c); and R^(c), when present, is as defined inany one of claims 33-35.

In some embodiments of [1], R² is as defined in any one of claims 24-31of U.S. 62/742,218, filed Oct. 5, 2018. In certain of the foregoingembodiments, R² is phenyl, which is optionally substituted with 2 R^(c),such as wherein R² is

and R^(c), when present, is as defined in any one of claims 33-35.

In certain embodiments of [1], R² is as defined in any one of claims27-31 of U.S. 62/742,218, filed Oct. 5, 2018. For example, R² can be

In some embodiments of [1], R² is heteroaryl including from 5-10 (suchas 6) ring atoms, wherein from 1-4 (such as 1-3) ring atoms areheteroatoms, each independently selected from the group consisting of N,N(H), N(R^(d)), O, and S (such as the group consisting of N, N(H), andN(R^(d))), and wherein one or more of the heteroaryl ring carbon atomsare optionally substituted with from 1-4 independently selected R^(c),such as wherein R² is pyridinyl which is optionally substituted withfrom 1-2 independently selected R^(c), or such as wherein R² is

and R^(c), when present, is as defined in any one of claims 40-41.

In certain embodiments of [1], R² is

In some embodiments of [1], R² is as defined in any one of claims 32-37of U.S. 62/742,218, filed Oct. 5, 2018. In certain of the foregoingembodiments, R² is as defined in any one of claims 34-37 of U.S.62/742,218, filed Oct. 5, 2018. For example, R² can be as defined inclaim 37 of U.S. 62/742,218, filed Oct. 5, 2018.

In some embodiments of [1] when one occurrence of R³ is -L⁴-R⁴, -L⁴ isselected from the group consisting of:

-   -   —N(H)S(O)₁₋₂— or —N(R^(d))S(O)₁₋₂ (e.g., N(C₁₋₃ alkyl)S(O)₂),        such as wherein L⁴ is —N(H)S(O)₂—;    -   —N(H)C(O)— or —N(R^(d))C(O), such as wherein L⁴ is —N(H)C(O)—;    -   —C(O)NH— or —C(O)N(R^(d))—;    -   —N(H)—, —N(R^(d))—, or —N(R⁴)—;    -   a single bond;    -   C≡C;    -   —O—; and    -   —N(H)S(O)₁₋₂N(H)—, —N(R^(d))S(O)₁₋₂N(H)—, —N(H)S(O)₁₋₂N(R^(d))—,        and —N(R^(d))S(O)₁₋₂N(R^(d))—, such as wherein L⁴ is        —N(H)S(O)₁₋₂N(H)— (e.g., —N(H)S(O)₂N(H)—) or wherein L⁴ is        —N(H)S(O)₁₋₂N(R^(d))— (e.g., —N(H)S(O)₂N(R^(d))— (e.g.,        —N(H)S(O)₂N(C₁₋₃ alkyl)-));

as well as defined in any one of claims 48-55 of U.S. 62/742,218, filedOct. 5, 2018.

In some embodiments of [1] when one occurrence of R³ is -L⁴-R⁴, -L⁴ isselected from the group consisting of:

-   -   —N(H)S(O)₁₋₂— or —N(R^(d))S(O)₁₋₂ (e.g., N(C₁₋₃ alkyl)S(O)₂),        such as wherein L⁴ is —N(H)S(O)₂—;    -   —N(H)C(O)— or —N(R^(d))C(O), such as wherein L⁴ is —N(H)C(O)—;    -   —C(O)NH— or —C(O)N(R^(d))—;    -   —N(H)—, —N(R^(d))—, or —N(R⁴)—;    -   a single bond; and    -   C≡C.

In some embodiments of [1] when one occurrence of R³ is -L⁴-R⁴, -L⁴ isselected from the group consisting of:

-   -   N(H)S(O)₂—;    -   —N(H)C(O)—; and    -   —N(H)—, —N(R^(d))—, or —N(R⁴)—.

In certain embodiments of [1], -L⁴ is as defined in any one of claims49, 51, and 53 of U.S. 62/742,218, filed Oct. 5, 2018. For example, L⁴can be as defined in claim 49 of U.S. 62/742,218, filed Oct. 5, 2018. Insome embodiments of [1] when one occurrence of R³ is -L⁴-R⁴, -L⁴ is—NHS(O)(═NH)—.

In some embodiments of [1] when one occurrence of R³ is -L⁴-R⁴, -L⁴ isselected from the group consisting of:

—N(H)S(O)₁₋₂— or —N(R^(d))S(O)₁₋₂ (e.g., N(C₁₋₃ alkyl)S(O)₂), such aswherein L⁴ is —N(H)S(O)₂—; and

—N(H)S(O)₁₋₂N(H)—, —N(R^(d))S(O)₁₋₂N(H)—, —N(H)S(O)₁₋₂N(R^(d))—, and—N(R^(d))S(O)₁₋₂N(R^(d))—, such as wherein L⁴ is —N(H)S(O)₁₋₂N(H)—(e.g., —N(H)S(O)₂N(H)—) or wherein L⁴ is —N(H)S(O)₁₋₂N(R^(d))— (e.g.,—N(H)S(O)₂N(R^(d))— (e.g., —N(H)S(O)₂N(C₁₋₃ alkyl)-)).

In some embodiments of [1] when one occurrence of R³ is -L⁴-R⁴; and R⁴is (Y³)_(p)—Y⁴, Y⁴ is C₆₋₁₀ aryl, which is optionally substituted withfrom 1-4 R^(c), such as phenyl, which is optionally substituted withfrom 1-2 (e.g., 1) R^(c), or wherein Y⁴ is unsubstituted C₆₋₁₀ aryl suchas unsubstituted phenyl; and R^(c), when present, is as defined in anyone of claims 73-75

In some embodiments of [1] when one occurrence of R³ is -L⁴-R⁴; and R⁴is (Y³)_(p)—Y⁴, Y⁴ is C₆₋₁₀ aryl, which is optionally substituted withfrom 1-4 R^(c), such as phenyl optionally substituted with from 1-4R^(c); and wherein each occurrence of R^(c), when present, isindependently selected from the group consisting of:

(vii) C₁₋₄ alkoxy;

(viii) C₁₋₄ haloalkoxy; and

(xiv) —C₁₋₄ thioalkoxy.

In some embodiments of [1] when one occurrence of R³ is -L⁴-R⁴; and R⁴is (Y³)_(p)—Y⁴, Y⁴ is as defined in any one of claims 77, 78, 79, 81,and 82, and wherein R^(b), when present, is as defined in claim 80.

In some embodiments of [1] when one occurrence of R³ is -L⁴-R⁴; and R⁴is (Y³)_(p)—Y⁴, Y⁴ is as defined in any one of claims 77-79; and R^(b),when present, is as defined in claim 80.

In some embodiments of [1] when one occurrence of R³ is -L⁴-R⁴; and R is(Y³)_(p)—Y⁴, Y⁴ is as defined in any one of claims 83-85 and 88; andR^(c), when present, is as defined in any one of claims 86-87.

In some embodiments of [1] when one occurrence of R³ is -L⁴-R⁴; and R⁴is (Y³)_(p)—Y⁴, Y⁴ is as defined in any one of claims 83-85, and 88.

In some embodiments of [1] when one occurrence of R³ is -L⁴-R⁴; and R⁴is (Y³)₉—Y⁴, Y⁴ is as defined in any one of claims 89-96; and R^(b),when present, is as defined in any one of claims 97-98.

In some embodiments of [1] when one occurrence of R³ is -L⁴-R⁴; and R⁴is (Y³)_(p)—Y⁴, Y⁴ is as defined in any one of claims 89-92, 94, and 96;and R^(b), when present, is as defined in claim 98.

In some embodiments of [1], R⁴ is selected from the group consisting ofthe structures delineated in claims 99-113.

In some embodiments of [1], R⁴ is selected from the group consisting ofthe structures delineated in claims 100, 101, 104-105, 107, 109, 111,and 113.

In some embodiments of [1] when one occurrence of R³ is -L⁴-R⁴,

-   -   R⁴ is C₁₋₁₀ alkyl, optionally substituted with from 1-6        independently selected R^(a); or    -   R⁴ is C₁₋₆ alkyl, optionally substituted with from 1-6        independently selected R^(a); or    -   R⁴ is C₁₋₆ alkyl, optionally substituted with from 1-2        independently selected R^(a), such as wherein R⁴ is selected        from the group consisting of: methyl, ethyl,

(such as methyl and

or

-   -   R⁴ is C₂₋₁₀ alkynyl (e.g., C₂₋₄ alkynyl), which is optionally        substituted with from 1-6 (e.g., from 1-3) independently        selected R^(a) (e.g., unsubstituted C₂₋₄ alkynyl such as

or

-   -   R⁴ is C₂₋₁₀ alkenyl (e.g., C₂₋₆ alkenyl), which is optionally        substituted with from 1-6 (e.g., from 1-3) independently        selected R^(a) (e.g., unsubstituted C₂₋₄ alkenyl such as vinyl);        and

wherein each R^(a), when present, is independently selected from thegroup consisting of: —F; —OH; C₁₋₄ alkoxy; and C₁₋₄ haloalkoxy, such aswherein each occurrence of R^(a) is independently —OH.

In some embodiments of [1] when one occurrence of R³ is -L⁴-R⁴,

-   -   R⁴ is C₁₋₁₀ alkyl, optionally substituted with from 1-6        independently selected R^(a); or    -   R⁴ is C₁₋₆ alkyl, optionally substituted with from 1-6        independently selected R^(a); or    -   R⁴ is C₁₋₆ alkyl, optionally substituted with from 1-2        independently selected R^(a), such as methyl and

and

wherein each R^(a), when present, is independently selected from thegroup consisting of: —F; —OH; C₁₋₄ alkoxy; and C₁₋₄ haloalkoxy, such as—OH.

In some embodiments of [1] when one occurrence of R³ is -L⁴-R⁴, R⁴ is asdefined in any one of claims 56-60 and 61-63 of U.S. 62/742,218, filedOct. 5, 2018.

In some embodiments of [1] when one occurrence of R³ is -L⁴-R⁴, R⁴ is asdefined in any one of claims 56-60 and 64-67 of U.S. 62/742,218, filedOct. 5, 2018.

In some embodiments of [1] when one occurrence of R³ is -L⁴-R⁴, R⁴ is asdefined in any one of claims 56-60 and 68-71 of U.S. 62/742,218, filedOct. 5, 2018.

In some embodiments of [1] when one occurrence of R³ is -L⁴-R⁴, R⁴ is asdefined in any one of claims 56-60 and 72-78 of U.S. 62/742,218, filedOct. 5, 2018.

In some embodiments of [1] when one occurrence of R³ is-L⁴-R⁴, R⁴ is asdefined in any one of claims 56-60 and 79-86 of U.S. 62/742,218, filedOct. 5, 2018.

In some embodiments of [1] when one occurrence of R³ is -L⁴-R⁴, R⁴ is asdefined in any one of claims 56-60 and 87-92 of U.S. 62/742,218, filedOct. 5, 2018.

In certain embodiments of [1], -L⁴ is selected from the group consistingof —N(H)S(O)₂—, —N(H)S(O)₂N(H)—, —N(H)S(O)₂N(R^(d))—, C≡C, a singlebond, —C(O)N(H)—, —N(H)—, —N(R⁴)—, —N(R^(d))—, and —N(H)C(O)—; and

R⁴ is selected from the group consisting of:

(i) C₁₋₆ alkyl optionally substituted with 1-2 R^(a);

(ii) —(Y³)_(p)—Y⁴; and

(iii) C₂₋₁₀ alkenyl or C₂₋₁₀ alkynyl, each of which is optionallysubstituted with from 1-3 independently selected R^(a).

In certain embodiments of [1], -L⁴ is selected from the group consistingof —N(H)S(O)₂—, —N(H)S(O)₂N(H)—, and —N(H)S(O)₂N(R^(d))—; and

R⁴ is selected from the group consisting of:

(i) C₁₋₆ alkyl optionally substituted with 1-2 R^(a);

(ii) —(Y³)_(p)—Y⁴; and

(iii) C₂₋₁₀ alkenyl or C₂₋₁₀ alkynyl, each of which is optionallysubstituted with from 1-3 independently selected R^(a).

In some embodiments of [1], R^(a) is selected from the group consistingof structures delineated in claims 148-165; or wherein R3 is selectedfrom the group consisting of structures delineated in claims 148-149,151, 153, 155-156, 158, 160, 162, and 165.

In some embodiments of [1], R³ is as defined in any one of claims113-122 of U.S. 62/742,218, filed Oct. 5, 2018.

[1-1]

In some embodiments of [1], each of X² and X³ is an independentlyselected CR³; and each of X¹ and X⁴ is independently N, or CH. Incertain of these embodiments, each of X¹ and X⁴ is N. In certain of theforegoing embodiments, each R³ is an independently selected -L⁴-R⁴.

In some embodiments of [1-1], one occurrence of -L⁴-R⁴ is —R⁴ (i.e., oneoccurrence of L⁴ is a bond).

In certain of these embodiments, the other occurrence of -L⁴ is selectedfrom the group consisting of:

-   -   —N(H)S(O)₁₋₂— or —N(R^(d))S(O)₁₋₂ (e.g., N(C₁₋₃ alkyl)S(O)₂),        such as wherein L⁴ is —N(H)S(O)₂—;    -   —N(H)C(O)— or —N(R^(d))C(O), such as wherein L⁴ is —N(H)C(O)—;    -   —C(O)NH— or —C(O)N(R^(d))—;    -   —N(H)—, —N(R^(d))—, or —N(R⁴)—;    -   a single bond;    -   C≡C;    -   —O—; and    -   —N(H)S(O)₁₋₂N(H)—, —N(R^(d))S(O)₁₋₂N(H)—, —N(H)S(O)₁₋₂N(R^(d))—,        and —N(R^(d))S(O)₁₋₂N(R^(d))—, such as wherein L⁴ is        —N(H)S(O)₁₋₂N(H)— (e.g., —N(H)S(O)₂N(H)—) or wherein L⁴ is        —N(H)S(O)₁₋₂N(R^(d))— (e.g., —N(H)S(O)₂N(R^(d))— (e.g.,        —N(H)S(O)₂N(C₁₋₃ alkyl)-)).

In certain embodiments, the other occurrence of -L⁴ is selected from thegroup consisting of:

-   -   —N(H)S(O)₁₋₂— or —N(R^(d))S(O)₁₋₂ (e.g., N(C₁₋₃ alkyl)S(O)₂),        such as wherein L⁴ is —N(H)S(O)₂—;    -   —N(H)C(O)— or —N(R^(d))C(O), such as wherein L⁴ is —N(H)C(O)—;    -   —C(O)NH— or —C(O)N(R^(d))—;

—N(H)—, —N(R^(d))—, or —N(R⁴)—;

-   -   a single bond; and    -   C≡C.

In certain embodiments, the other occurrence of -L⁴ is selected from thegroup consisting of:

-   -   —N(H)S(O)₂—;    -   —N(H)C(O)—; and    -   —N(H)—, —N(R^(d))—, or —N(R⁴)—, such as wherein the other        occurrence of -L⁴ is N(H)S(O)₂—.

In certain embodiments, the other occurrence of -L⁴ is selected from thegroup consisting of:

—N(H)S(O)₁₋₂— or —N(R^(d))S(O)₁₋₂ (e.g., N(C₁₋₃ alkyl)S(O)₂), such aswherein L⁴ is —N(H)S(O)₂—; and

—N(H)S(O)₁₋₂N(H)—, —N(R^(d))S(O)₁₋₂N(H)—, —N(H)S(O)₁₋₂N(R^(d))—, and—N(R^(d))S(O)₁₋₂N(R^(d))—, such as wherein L⁴ is —N(H)S(O)₁₋₂N(H)—(e.g., —N(H)S(O)₂N(H)—) or wherein L⁴ is —N(H)S(O)₁₋₂N(R^(d))— (e.g.,—N(H)S(O)₂N(R^(d))— (e.g., —N(H)S(O)₂N(C₁₋₃ alkyl)-)).

In certain of the foregoing embodiments, the other occurrence of -L⁴ isas defined in any one of claims defined in claims 48-55 of U.S.62/742,218, filed Oct. 5, 2018. For example, the other occurrence of -L⁴can be as defined in any one of claims 49, 51, and 53 (e.g., claim 49)of U.S. 62/742,218, filed Oct. 5, 2018.

In some embodiments of [1-1], each R⁴ is independently as defined in anyone of claims 56-60 and 61-63 of U.S. 62/742,218, filed Oct. 5, 2018.

In some embodiments of [1-1], each R⁴ is independently as defined in anyone of claims 56-60 and 64-67 of U.S. 62/742,218, filed Oct. 5, 2018.

In some embodiments of [1-1], each R⁴ is independently as defined in anyone of claims 56-60 and 68-71 of U.S. 62/742,218, filed Oct. 5, 2018.

In some embodiments of [1-1], each R⁴ is independently as defined in anyone of claims 56-60 and 72-78 of U.S. 62/742,218, filed Oct. 5, 2018.

In some embodiments of [1-1], each R⁴ is independently as defined in anyone of claims 79-86 of U.S. 62/742,218, filed Oct. 5, 2018.

In some embodiments of [1-1], each R⁴ is independently as defined in anyone of claims 87-92 of U.S. 62/742,218, filed Oct. 5, 2018.

In some embodiments of [1-1], R¹ is as defined in any one of claims10-23 of U.S. 62/742,218, filed Oct. 5, 2018.

In some embodiments of [1-1], R¹ is as defined in any one of claims16-23 of U.S. 62/742,218, filed Oct. 5, 2018.

In some embodiments of [1-1], R¹ is as defined in claim 23 of U.S.62/742,218, filed Oct. 5, 2018.

In some embodiments of [1-1], R² is as defined in any one of claims24-31 of U.S. 62/742,218, filed Oct. 5, 2018.

In some embodiments of [1-1], R² is as defined in any one of claims27-31 of U.S. 62/742,218, filed Oct. 5, 2018.

In some embodiments of [1-1], R² is as defined in any one of claims32-37 (e.g., 34-37) of U.S. 62/742,218, filed Oct. 5, 2018.

[1-2]

In some embodiments of [1], each of X² and X³ is an independentlyselected CR³; and each of X¹ and X⁴ is independently N, or CH. Incertain of these embodiments, each of X¹ and X⁴ is N.

In some embodiments of [1-2], one occurrence of R³ is -L⁴-R⁴ (e.g., -L⁴is as defined in claim 49); and the other occurrence of R³ is R^(c′)(e.g., R^(c′) can be halo such as —Cl).

In certain of these embodiments, -L⁴ is selected from the groupconsisting of:

-   -   —N(H)S(O)₁₋₂— or —N(R^(d))S(O)₁₋₂ (e.g., N(C₁₋₃ alkyl)S(O)₂),        such as wherein L⁴ is —N(H)S(O)₂—;    -   —N(H)C(O)— or —N(R^(d))C(O), such as wherein L⁴ is —N(H)C(O)—;    -   —C(O)NH— or —C(O)N(R^(d))—;    -   —N(H)—, —N(R^(d))—, or —N(R⁴)—;    -   a single bond;    -   C≡C;    -   —O—; and    -   —N(H)S(O)₁₋₂N(H)—, —N(R^(d))S(O)₁₋₂N(H)—, —N(H)S(O)₁₋₂N(R^(d))—,        and —N(R^(d))S(O)₁₋₂N(R^(d))—, such as wherein L⁴ is        —N(H)S(O)₁₋₂N(H)— (e.g., —N(H)S(O)₂N(H)—) or wherein L⁴ is        —N(H)S(O)₁₋₂N(R^(d))— (e.g., —N(H)S(O)₂N(R^(d))— (e.g.,        —N(H)S(O)₂N(C₁₋₃ alkyl)-)).

In certain embodiments, -L⁴ is selected from the group consisting of:

-   -   —N(H)S(O)₁₋₂— or —N(R^(d))S(O)₁₋₂ (e.g., N(C₁₋₃ alkyl)S(O)₂),        such as wherein L⁴ is —N(H)S(O)₂—;    -   —N(H)C(O)— or —N(R^(d))C(O), such as wherein L⁴ is —N(H)C(O)—;    -   —C(O)NH— or —C(O)N(R^(d))—;    -   —N(H)—, —N(R^(d))—, or —N(R⁴)—;    -   a single bond; and    -   C≡C.

In certain embodiments, -L⁴ is selected from the group consisting of:

-   -   —N(H)S(O)₂—;    -   —N(H)C(O)—; and    -   —N(H)—, —N(R^(d))—, or —N(R⁴)—, such as wherein the other        occurrence of -L⁴ is N(H)S(O)₂—.

In certain embodiments, -L⁴ is selected from the group consisting of:

-   -   —N(H)S(O)₁₋₂— or —N(R^(d))S(O)₁₋₂ (e.g., N(C₁₋₃ alkyl)S(O)₂),        such as wherein L⁴ is —N(H)S(O)₂—; and    -   —N(H)S(O)₁₋₂N(H)—, —N(R^(d))S(O)₁₋₂N(H)—, —N(H)S(O)₁₋₂N(R^(d))—,        and —N(R^(d))S(O)₁₋₂N(R^(d))—, such as wherein L⁴ is        —N(H)S(O)₁₋₂N(H)— (e.g., —N(H)S(O)₂N(H)—) or wherein L⁴ is        —N(H)S(O)₁₋₂N(R^(d))— (e.g., —N(H)S(O)₂N(R^(d))— (e.g.,        —N(H)S(O)₂N(C₁₋₃ alkyl)-)).

In certain of the foregoing embodiments, the other occurrence of -L⁴ isas defined in any one of claims defined in claims 48-55 of U.S.62/742,218, filed Oct. 5, 2018. For example, the other occurrence of -L⁴can be as defined in any one of claims 49, 51, and 53 (e.g., claim 49)of U.S. 62/742,218, filed Oct. 5, 2018.

In some embodiments of [1-2], each R⁴ is independently as defined in anyone of claims 56-60 and 61-63 of U.S. 62/742,218, filed Oct. 5, 2018.

In some embodiments of [1-2], each R⁴ is independently as defined in anyone of claims 56-60 and 64-67 of U.S. 62/742,218, filed Oct. 5, 2018.

In some embodiments of [1-2], each R⁴ is independently as defined in anyone of claims 56-60 and 68-71 of U.S. 62/742,218, filed Oct. 5, 2018.

In some embodiments of [1-2], each R⁴ is independently as defined in anyone of claims 56-60 and 72-78 of U.S. 62/742,218, filed Oct. 5, 2018.

In some embodiments of [1-2], each R⁴ is independently as defined in anyone of claims 79-86 of U.S. 62/742,218, filed Oct. 5, 2018.

In some embodiments of [1-2], each R⁴ is independently as defined in anyone of claims 87-92 of U.S. 62/742,218, filed Oct. 5, 2018.

In some embodiments of [1-2], R¹ is as defined in any one of claims10-23 of U.S. 62/742,218, filed Oct. 5, 2018.

In some embodiments of [1-2], R¹ is as defined in any one of claims16-23 of U.S. 62/742,218, filed Oct. 5, 2018.

In some embodiments of [1-2], R¹ is as defined in claim 23 of U.S.62/742,218, filed Oct. 5, 2018.

In some embodiments of [1-2], R² is as defined in any one of claims24-31 of U.S. 62/742,218, filed Oct. 5, 2018.

In some embodiments of [1-2], R² is as defined in any one of claims27-31 of U.S. 62/742,218, filed Oct. 5, 2018.

In some embodiments of [1-2], R² is as defined in any one of claims32-37 (e.g., 34-37) of U.S. 62/742,218, filed Oct. 5, 2018.

Non-Limiting Combinations [2]

In some embodiments, a compound of Formula (I) is of Formula (I-a1-a):

or a pharmaceutically acceptable salt thereof.

In some embodiments of [2], -L⁴ is selected from the group consistingof:

—N(H)S(O)₁₋₂— or —N(R^(d))S(O)₁₋₂ (e.g., N(C₁₋₃ alkyl)S(O)₂), such aswherein L⁴ is —N(H)S(O)₂—; and

—N(H)S(O)₁₋₂N(H)—, —N(R^(d))S(O)₁₋₂N(H)—, —N(H)S(O)₁₋₂N(R^(d))—, and—N(R^(d))S(O)₁₋₂N(R^(d))—, such as wherein L is —N(H)S(O)₁₋₂N(H)— (e.g.,—N(H)S(O)₂N(H)—) or wherein L⁴ is —N(H)S(O)₁₋₂N(R^(d))— (e.g.,—N(H)S(O)₂N(R^(d))— (e.g., —N(H)S(O)₂N(C₁₋₃ alkyl)-)).

In certain embodiments of [2], a compound of Formula (I-a1-a) is ofFormula (I-a1-a1):

or a pharmaceutically acceptable salt thereof.

In certain embodiments of [2], a compound of Formula (I-a1-a) is ofFormula (I-a1-a2):

or a pharmaceutically acceptable salt thereof.

In certain embodiments of [2], a compound of Formula (I-a1-a) is ofFormula (I-a1-a3):

(e.g., R^(c′) is halo, e.g., —Cl);or a pharmaceutically acceptable salt thereof.

In certain of the foregoing embodiments of [2], R¹ is as defined in anyone of claims 10-23 of U.S. 62/742,218, filed Oct. 5, 2018; and/or R² isas defined in any one of claims 24-37 of U.S. 62/742,218, filed Oct. 5,2018; and/or R⁴ is as defined in any one of claims 56-92 of U.S.62/742,218, filed Oct. 5, 2018.

In certain embodiments of [2], a compound of Formula (I-a1-a) is ofFormula (I-a1-a4):

(e.g., R³ is R^(c′); or R³ is -L⁴-R⁴);or a pharmaceutically acceptable salt thereof.

In certain embodiments of Formula (I-a1-a4), L³ is NHS(O)₂.

In certain embodiments of Formula (I-a1-a4), R³ is H.

In certain embodiments of Formula (I-a1-a4), R³ is R^(c′), such as halo(e.g., —Cl).

In certain embodiments of Formula (I-a1-a4), R³ is -L⁴-R⁴.

In certain of the foregoing embodiments of [2] (e.g., when the compoundhas Formula (I-a1-a4)), L⁴ is as defined in any one of claims 48-55 ofU.S. 62/742,218, filed Oct. 5, 2018; and/or R⁴ is as defined in any oneof claims 56-60 of U.S. 62/742,218, filed Oct. 5, 2018 and 61-63 of U.S.62/742,218, filed Oct. 5, 2018; or 56-60 of U.S. 62/742,218, filed Oct.5, 2018 and 64-67 of U.S. 62/742,218, filed Oct. 5, 2018; or 56-60 ofU.S. 62/742,218, filed Oct. 5, 2018 and 68-71 of U.S. 62/742,218, filedOct. 5, 2018; or 56-60 and 72-78 of U.S. 62/742,218, filed Oct. 5, 2018;or 79-86 of U.S. 62/742,218, filed Oct. 5, 2018; or 87-92 of U.S.62/742,218, filed Oct. 5, 2018.

[2-1]

In some embodiments of [2], the compound of Formula (I-a1-a) is ofFormula (I-a1-a5):

or a pharmaceutically acceptable salt thereof.

In some embodiments of [2-1], R^(c′) is halo (e.g., —Cl).

In some embodiments of [2-1], R¹ is as defined in any one of claims10-23 of U.S. 62/742,218, filed Oct. 5, 2018.

In some embodiments of [2-1], R² is as defined in any one of claims24-37 (e.g., claims 24-31) of U.S. 62/742,218, filed Oct. 5, 2018.

In some embodiments of [2-1], R⁴ is as defined in any one of claims56-92 (e.g., claims 87-92) of U.S. 62/742,218, filed Oct. 5, 2018. Insome embodiments of [2-1], L⁴ is —NHS(O)₂—.

In some embodiments of [2-1], L⁴ is —N(H)S(O)₂N(H)— or—N(H)S(O)₂N(R^(d))—.

[2-2]

In some embodiments of [2], compound of Formula (I-a1-a) is of Formula(I-a1-a6):

wherein each of L^(4A) and L^(4B) is an independently selected L⁴; andeach of R^(4A) and R^(4B) is an independently selected R⁴;or a pharmaceutically acceptable salt thereof.

In some embodiments of [2-2], L^(4B) is a bond.

In some embodiments of [2-2], R¹ is as defined in any one of claims10-23 of U.S. 62/742,218, filed Oct. 5, 2018.

In some embodiments of [2-2], R² is as defined in any one of claims24-37 (e.g., claims 24-31) of U.S. 62/742,218, filed Oct. 5, 2018.

In some embodiments of [2-2], R⁴ is as defined in any one of claims56-92 of U.S. 62/742,218, filed Oct. 5, 2018.

In some embodiments of [2-2], L^(4A) is —NHS(O)₂—.

In some embodiments of [2-2], L⁴ is —N(H)S(O)₂N(H)— or—N(H)S(O)₂N(R^(d))—.

In some embodiments of [2-2], R^(4B) is as defined in any one of claims56-92 (e.g., claims 56-60 and 64-67) of U.S. 62/742,218, filed Oct. 5,2018.

[2-3]

In some embodiments of [2], compound of Formula (I-a1-a) is of Formula(I-a1-a7), (I-a1-a8) or (I-a1-a9):

wherein R^(d′) is H or R^(d) (e.g., H or C₁₋₃ alkyl); or apharmaceutically acceptable salt thereof.

Non-Limiting Combinations [3]

In some embodiments, a compound of Formula (I) is of Formula (I-a1-b):

or a pharmaceutically acceptable salt thereof.

In certain embodiments of [3], a compound of Formula (I-a1-b) is ofFormula (I-a1-b1) or Formula (I-a1-b2):

(e.g., L⁴ is N(H)SO₂, —N(H)—, or NHC(O));

or a pharmaceutically acceptable salt thereof.

In some embodiments of [3], -L⁴ is selected from the group consistingof:

—N(H)S(O)₁₋₂— or —N(R^(d))S(O)₁₋₂ (e.g., N(C₁₋₃ alkyl)S(O)₂), such aswherein L⁴ is —N(H)S(O)₂—; and

—N(H)S(O)₁₋₂N(H)—, —N(R^(d))S(O)₁₋₂N(H)—, —N(H)S(O)₁₋₂N(R^(d))—, and—N(R^(d))S(O)₁₋₂N(R^(d))—, such as wherein L⁴ is —N(H)S(O)₁₋₂N(H)—(e.g., —N(H)S(O)₂N(H)—) or wherein L⁴ is —N(H)S(O)₁₋₂N(R^(d))— (e.g.,—N(H)S(O)₂N(R^(d))— (e.g., —N(H)S(O)₂N(C₁₋₃ alkyl)-)).

In certain of the foregoing embodiments of [3], R¹ is as defined in anyone of claims 10-23 of U.S. 62/742,218, filed Oct. 5, 2018; and/or R² isas defined in any one of claims 24-37 of U.S. 62/742,218, filed Oct. 5,2018; and/or R⁴ is as defined in any one of claims 56-92 of U.S.62/742,218, filed Oct. 5, 2018.

In certain of the foregoing embodiments of [3], R^(c′) is selected fromhalo (e.g., Cl, Br), —OH, and NH₂.

Non-Limiting Combinations [4]

In some embodiments, a compound of Formula (I) is of Formula (I-a2-a):

or a pharmaceutically acceptable salt thereof.

In certain embodiments of [4], a compound of Formula (I-a2-a1) is acompound of Formula (I-a2-a1):

or a pharmaceutically acceptable salt thereof.

In certain of the foregoing embodiments of [4], R¹ is as defined in anyone of claims 10-23 of U.S. 62/742,218, filed Oct. 5, 2018; and/or R² isas defined in any one of claims 24-37 of U.S. 62/742,218, filed Oct. 5,2018; and/or R⁴ is as defined in any one of claims 56-92 of U.S.62/742,218, filed Oct. 5, 2018.

In certain embodiments of [4], a compound of Formula (I-a2-a) is ofFormula (I-a1-a2):

(e.g., L⁴ is NHS(O)₂);or a pharmaceutically acceptable salt thereof.

In certain of the foregoing embodiments of [4] (e.g., when the compoundhas Formula (I-a2-a2)), L⁴ is as defined in any one of claims 48-55(e.g., 49) of U.S. 62/742,218, filed Oct. 5, 2018; and/or R⁴ is asdefined in any one of claims 56-60 of U.S. 62/742,218, filed Oct. 5,2018 and 61-63 of U.S. 62/742,218, filed Oct. 5, 2018; or 56-60 of U.S.62/742,218, filed Oct. 5, 2018 and 64-67 of U.S. 62/742,218, filed Oct.5, 2018; or 56-60 of U.S. 62/742,218, filed Oct. 5, 2018 and 68-71 ofU.S. 62/742,218, filed Oct. 5, 2018; or 56-60 of U.S. 62/742,218, filedOct. 5, 2018 and 72-78 of U.S. 62/742,218, filed Oct. 5, 2018; or 79-86of U.S. 62/742,218, filed Oct. 5, 2018; or 87-92 of U.S. 62/742,218,filed Oct. 5, 2018.

Non-Limiting Combinations [5]

In some embodiments, a compound of Formula (I) is of Formula (I-b1-a):

or a pharmaceutically acceptable salt thereof.

In certain embodiments of [5], a compound of Formula (I-b1-a) is ofFormula (I-b1-a1):

or a pharmaceutically acceptable salt thereof.

In certain of the foregoing embodiments of [5], R¹ is as defined in anyone of claims 10-23 of U.S. 62/742,218, filed Oct. 5, 2018; and/or R² isas defined in any one of claims 24-37 of U.S. 62/742,218, filed Oct. 5,2018; and/or R⁴ is as defined in any one of claims 56-92 of U.S.62/742,218, filed Oct. 5, 2018.

In certain embodiments of [5], a compound of Formula (I-b1-a) is ofFormula (I-b1-a3):

wherein R^(d′) is H or R^(d)(e.g., H or C₁₋₃ alkyl); or apharmaceutically acceptable salt thereof.

In certain embodiments of [5], a compound of Formula (I-b1-a) of Formula(I-b1-a2):

e.g., L is NHS(O)₂);or a pharmaceutically acceptable salt thereof.

In certain embodiments of Formula (I-b1-a2), L⁴ is NHS(O)₂.

In certain of the foregoing embodiments of [5] (e.g., when the compoundhas Formula (I-b1-a2)), L⁴ is as defined in any one of claims 48-55(e.g., 49) of U.S. 62/742,218, filed Oct. 5, 2018; and/or R⁴ is asdefined in any one of claims 56-60 of U.S. 62/742,218, filed Oct. 5,2018 and 61-63 of U.S. 62/742,218, filed Oct. 5, 2018; or 56-60 of U.S.62/742,218, filed Oct. 5, 2018 and 64-67 of U.S. 62/742,218, filed Oct.5, 2018; or 56-60 of U.S. 62/742,218, filed Oct. 5, 2018 and 68-71 ofU.S. 62/742,218, filed Oct. 5, 2018; or 56-60 of U.S. 62/742,218, filedOct. 5, 2018 and 72-78 of U.S. 62/742,218, filed Oct. 5, 2018; or 79-86of U.S. 62/742,218, filed Oct. 5, 2018; or 87-92 of U.S. 62/742,218,filed Oct. 5, 2018.

Non-Limiting Combinations [6]

In some embodiments, a compound of Formula (I) is of Formula (I-c1-a):

or a pharmaceutically acceptable salt thereof.

In certain embodiments of [6], a compound of Formula (I-c1-a) is ofFormula (I-c1-a1):

or a pharmaceutically acceptable salt thereof.

In certain of the foregoing embodiments of [6], R¹ is as defined in anyone of claims 10-23 of U.S. 62/742,218, filed Oct. 5, 2018; and/or R² isas defined in any one of claims 24-37 of U.S. 62/742,218, filed Oct. 5,2018; and/or R⁴ is as defined in any one of claims 56-92 of U.S.62/742,218, filed Oct. 5, 2018.

In certain embodiments of [6], a compound of Formula (I-c1-a) of Formula(I-c1-a2):

(e.g., L⁴ is NHS(O)₂);or a pharmaceutically acceptable salt thereof.

In certain of the foregoing embodiments of [6] (e.g., when the compoundhas Formula (I-c1-a2)), L⁴ is as defined in any one of claims 48-55(e.g., 49) of U.S. 62/742,218, filed Oct. 5, 2018; and/or R⁴ is asdefined in any one of claims 56-60 of U.S. 62/742,218, filed Oct. 5,2018 and 61-63 of U.S. 62/742,218, filed Oct. 5, 2018; or 56-60 of U.S.62/742,218, filed Oct. 5, 2018 and 64-67 of U.S. 62/742,218, filed Oct.5, 2018; or 56-60 of U.S. 62/742,218, filed Oct. 5, 2018 and 68-71 ofU.S. 62/742,218, filed Oct. 5, 2018; or 56-60 of U.S. 62/742,218, filedOct. 5, 2018 and 72-78 of U.S. 62/742,218, filed Oct. 5, 2018; or 79-86of U.S. 62/742,218, filed Oct. 5, 2018; or 87-92 of U.S. 62/742,218,filed Oct. 5, 2018.

Non-Limiting Combinations [7]

In some embodiments, the compound of Formula (I) is of Formula (I-d1-a):

or a pharmaceutically acceptable salt thereof.

In certain embodiments of [7], the compound of Formula (I-d1-a) is ofFormula (I-d1-a1):

or a pharmaceutically acceptable salt thereof.

In certain embodiments of [7], R¹ is as defined in any one of claims10-23 of U.S. 62/742,218, filed Oct. 5, 2018; and/or R² is as defined inany one of claims 24-37 of U.S. 62/742,218, filed Oct. 5, 2018; and/orR⁴ is as defined in any one of claims 56-92 of U.S. 62/742,218, filedOct. 5, 2018.

In certain embodiments of [7], a compound of Formula (I-d1-a) of Formula(I-d1-a2):

(e.g., L⁴ is NHS(O)₂);or a pharmaceutically acceptable salt thereof.

In certain of the foregoing embodiments of [7] (e.g., when the compoundhas Formula (I-c1-a2)), L⁴ is as defined in any one of claims 48-55(e.g., 49) of U.S. 62/742,218, filed Oct. 5, 2018; and/or R⁴ is asdefined in any one of claims 56-60 of U.S. 62/742,218, filed Oct. 5,2018 and 61-63 of U.S. 62/742,218, filed Oct. 5, 2018; or 56-60 of U.S.62/742,218, filed Oct. 5, 2018 and 64-67 of U.S. 62/742,218, filed Oct.5, 2018; or 56-60 of U.S. 62/742,218, filed Oct. 5, 2018 and 68-71 ofU.S. 62/742,218, filed Oct. 5, 2018; or 56-60 of U.S. 62/742,218, filedOct. 5, 2018 and 72-78 of U.S. 62/742,218, filed Oct. 5, 2018; or 79-86of U.S. 62/742,218, filed Oct. 5, 2018; or 87-92 of U.S. 62/742,218,filed Oct. 5, 2018.

In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1],[2-2], [2-3], [3], [4], [5], [6], and [7], R⁴ is selected from the groupconsisting of:

(i) C₁₋₁₀ alkyl, optionally substituted with from 1-6 independentlyselected R^(a);

(ii) —(Y³)_(p)—Y⁴; and

(iii) C₂₋₁₀ alkenyl or C₂₋₁₀ alkynyl, each of which is optionallysubstituted with from 1-3 independently selected R^(a).

In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1],[2-2], [2-3], [3], [4], [5], [6], and [7], R⁴ is —(Y³)_(p)—Y⁴.

In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1],[2-2], [2-3], [3], [4], [5], [6], and [7] when R⁴ is —(Y³)_(p)—Y⁴, Y⁴ isC₆₋₁₀ aryl, which is optionally substituted with from 1-4 R^(c), such asphenyl, which is optionally substituted with from 1-2 (e.g., 1) R^(c),or wherein Y⁴ is unsubstituted C₆₋₁₀ aryl such as unsubstituted phenyl;and R^(c), when present, is as defined in any one of claims 73-75 (e.g.,claim 75).

In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1],[2-2], [2-3], [3], [4], [5], [6], and [7] when R⁴ is —(Y³)_(p)—Y⁴, Y⁴ isC₆₋₁₀ aryl, which is optionally substituted with from 1-4 R^(c), such asphenyl optionally substituted with from 1-4 R^(c); and wherein eachoccurrence of R^(c), when present, is independently selected from thegroup consisting of:

(vii) C₁₋₄ alkoxy;

(viii) C₁₋₄ haloalkoxy; and

(xiv) —C₁₋₄ thioalkoxy.

In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1],[2-2], [2-3], [3], [4], [5], [6], and [7] when R⁴ is —(Y³)_(p)—Y⁴, Y⁴ isas defined in any one of claims 77, 78, 79, 81, and 82, and whereinR^(b), when present, is as defined in claim 80.

In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1],[2-2], [2-3], [3], [4], [5], [6], and [7] when R⁴ is —(Y³)_(p)—Y⁴, Y⁴ isas defined in any one of claims 77-79; and R^(b), when present, is asdefined in claim 80.

In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1],[2-2], [2-3], [3], [4], [5], [6], and [7] when R⁴ is —(Y³)_(p)—Y⁴, Y⁴ isas defined in any one of claims 83-85 and 88; and R^(c), when present,is as defined in any one of claims 86-87.

In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1],[2-2], [2-3], [3], [4], [5], [6], and [7] when R⁴ is —(Y³)_(p)—Y⁴, Y⁴ isas defined in any one of claims 83-85, and 88.

In certain embodiments of any one or more of [1-1], [1-2], [2], 12-11,12-21, [2-3], [3], [4], [5], [6], and [7] when R⁴ is —(Y³)_(p)—Y⁴, Y⁴ isas defined in any one of claims 89-96; and R^(b), when present, is asdefined in any one of claims 97-98.

In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1],[2-2], [2-3], [3], [4], [5], [6], and [7] when R⁴ is —(Y³)_(p)—Y⁴, Y⁴ isas defined in any one of claims 89-92, 94, and 96; and R^(b), whenpresent, is as defined in claim 98.

In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1],[2-2], [2-3], [3], [4], [5], [6], and [7] when R⁴ is —(Y³)_(p)—Y⁴, p is0.

In other embodiments, p is 1. In certain of these embodiments, Y³ isC₁₋₃ alkylene, such as CH₂ or CH₂—CH₂.

In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1],[2-2], [2-3], [3], [4], [5], [6], and [7], R⁴ is selected from the groupconsisting of the structures delineated in claims 99-113.

In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1],[2-2], [2-3], [3], [4], [5], [6], and [7], each R⁴ is selected from thegroup consisting of the structures delineated in claims 100, 101,104-105, 107, 109, 111, and 113.

In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1],[2-2], [2-3], [3], [4], [5], [6], and [7],

-   -   R⁴ is C₁₋₁₀ alkyl, optionally substituted with from 1-6        independently selected R^(a); or    -   R⁴ is C₁₋₆ alkyl, optionally substituted with from 1-6        independently selected R^(a); or    -   R⁴ is C₁₋₆ alkyl, optionally substituted with from 1-2        independently selected R^(a), such as wherein R⁴ is selected        from the group consisting of: methyl, ethyl,

(such as methyl and

or

-   -   R⁴ is C₂₋₁₀ (e.g., C₂₋₄ alkynyl) alkynyl, which is optionally        substituted with from 1-6 (e.g., from 1-3) independently        selected R^(a) (e.g., unsubstituted C₂₋₄ alkynyl such as

or

-   -   R⁴ is C₂₋₁₀ (e.g., C₂₋₄ alkenyl) alkenyl, which is optionally        substituted with from 1-6 (e.g., from 1-3) independently        selected R^(a) (e.g., unsubstituted C₂₋₄ alkenyl such as vinyl);        and

wherein each R^(a), when present, is independently selected from thegroup consisting of: —F; —OH; C₁₋₄ alkoxy; and C₁₋₄ haloalkoxy, such aswherein each occurrence of R¹ is independently —OH.

In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1],[2-2], [2-3], [3], [4], [5], [6], and [7],

-   -   R⁴ is C₁₋₁₀ alkyl, optionally substituted with from 1-6        independently selected R^(a); or    -   R⁴ is C₁₋₆ alkyl, optionally substituted with from 1-6        independently selected R^(a); or    -   R⁴ is C₁₋₆ alkyl, optionally substituted with from 1-2        independently selected R^(a), such as methyl

and

-   -   wherein each R^(a), when present, is independently selected from        the group consisting of: —F; —OH; C₁₋₄ alkoxy; and C₁₋₄        haloalkoxy, such as —OH.

In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1],[2-2], [2-3], [3], [4], [5], [6], and [7], R¹ is —(Y¹)_(n)—Y².

In certain of these embodiments, Y² is as defined in any one of claims14-20; and each R^(c), when present, is independently as defined in anyone of claims 21-24.

In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1],[2-2], [2-3], [3], [4], [5], [6], and [7] when R¹ is —(Y¹)_(n)—Y², Y² isas defined in any one of claims 14-18 and 26; and each R^(d), whenpresent, is as defined in any one of claims 21-23.

In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1],[2-2], [2-3], [3], [4], [5], [6], and [7] when R¹ is —(Y¹)_(n)—Y², Y² isas defined in any one of claims 16-18; and each R^(c), when present, isas defined in any one of claims 21-23.

In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1],[2-2], [2-3], [3], [4], [5], [6], and [7] when R¹ is —(Y¹)_(n)—Y², n is0.

In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1],[2-2], [2-3], [3], [4], [5], [6], and [7] when R¹ is —(Y¹)_(n)—Y², R¹ is

As a non-limiting example, R¹ can be

In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1],[2-2], [2-3], [3], [4], [5], [6], and [7], R² is C₆₋₁₀ aryl, which isoptionally substituted with from 1-4 R^(c), such as phenyl, which isoptionally substituted with from 1-4 R^(c) or 1-2 R^(c) or 2 R^(c); andR^(c), when present, is as defined in any one of claims 33-35.

In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1],[2-2], [2-3], [3], [4], [5], [6], and [7], R² is phenyl, which isoptionally substituted with 2 R^(c), such as wherein R² is

and R^(c), when present, is as defined in any one of claims 33-35.

In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1],[2-2], [2-3], [3], [4], [5], [6], and [7], R² is heteroaryl includingfrom 5-10 (such as 6) ring atoms, wherein from 1-4 (such as 1-3) ringatoms are heteroatoms, each independently selected from the groupconsisting of N, N(H), N(R^(d)), O, and S (such as the group consistingof N, N(H), N(R^(d)), and O), and wherein one or more of the heteroarylring carbon atoms are optionally substituted with from 1-4 independentlyselected R^(c), such as wherein R² is pyridinyl which is optionallysubstituted with from 1-2 independently selected R^(c), or such aswherein R² is

and R^(c), when present, is as defined in any one of claims 40-41.

In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1],[2-2], [2-3], [3], [4], [5], [6], and [7], R² is

In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1],[2-2], [2-3], [3], [4], [5], [6], and [7], R¹ is —(Y¹)_(n)—Y²; and R² isC₆₋₁₀ aryl, which is optionally substituted with from 1-4 R^(c).

In certain of these embodiments, n is 0.

In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1],[2-2], [2-3], [3], [4], [5], [6], and [7] when R¹ is —(Y¹)_(n)—Y², Y² isheteroaryl including 6 ring atoms, wherein from 1-2 ring atoms are N,and wherein one or more of the heteroaryl ring carbon atoms areoptionally substituted with from 1-4 independently selected R^(c).

In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1],[2-2], [2-3], [3], [4], [5], [6], and [7] when R¹ is —(Y¹)_(n)—Y², Y² ispyridyl (e.g., 2-pyridyl or 6-pyridyl), wherein one or more of the ringcarbon atoms are optionally substituted with from 1-4 (e.g., 1)independently selected R^(c).

In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1],[2-2], [2-3], [3], [4], [5], [6], and [7] when R¹ is —(Y¹)_(n)—Y²; andY² is heteroaryl such as pyridyl optionally substituted with 1-4independently selected R^(c) as defined supra, each occurrence of R^(c)is an independently selected C₁₋₄ alkoxy (e.g., —OCH₃, —OCH₂CH₃).

As a non-limiting example, R¹ is:

In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1],[2-2], [2-3], [3], [4], [5], [6], and [7] (when R¹ is —(Y¹)_(n)—Y²; andR² is C₆₋₁₀ aryl, which is optionally substituted with from 1-4 R^(c)),such as R² is phenyl, which is optionally substituted with from 1-4R^(c).

In certain of these embodiments, R² is phenyl, which is optionallysubstituted with 2 R^(c). For example, R² can be:

In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1],[2-2], [2-3], [3], [4], [5], [6], and [7], R¹ is

and R² is

This specification concludes with 302 claims. For ease of exposition,certain variable definitions refer to one or more specific claimnumbers, and as such, it is understood that the entire subject matter ofeach claim referenced is incorporated by reference in its entirety intothe portion of the disclosure, in which it is referenced. For theavoidance of doubt and as a non-limiting example, use of a phrase, suchas “Y⁴ is as defined in any one of claims 77, 78, 79, 81, and 82” isintended to represent a short-hand recitation for the following set ofdefintions:

Y⁴ is C₃₋₆ (e.g., C₃₋₄ or C₆) cycloalkyl, which is optionallysubstituted with from 1-4 R^(b).

Y⁴ is cyclopropyl or cyclobutyl which is optionally substituted withfrom 1-2 R^(b).

Y⁴ is C₆ cycloalkyl (e.g., cyclohexyl), which is optionally substitutedwith from 1-2 R^(b).

Y⁴ is C₃₋₆ (e.g., C₃₋₆ or C₆) cycloalkyl, which is unsubstituted.

Y⁴ is unsubstituted cyclopropyl or unsubstituted cyclobutyl (e.g.,unsubstituted cyclopropyl).

Y⁴ is selected from the group consisting of C₃₋₆ (e.g., C₃₋₄ or C₆)cycloalkyl, which is optionally substituted with from 1-4 R^(b);cyclopropyl or cyclobutyl which is optionally substituted with from 1-2R^(b); C₆ cycloalkyl (e.g., cyclohexyl), which is optionally substitutedwith from 1-2 R^(b); is C₃₋₆ (e.g., C₃₋₄ or C₆) cycloalkyl, which isunsubstituted; and unsubstituted cyclopropyl or unsubstituted cyclobutyl(e.g., unsubstituted cyclopropyl).

The same also applies to claims referenced from the priority documentU.S. 62/742,218, filed on Oct. 5, 2018.

Pharmaceutical Compositions and Administration

General

In some embodiments, a chemical entity (e.g., a compound or apharmaceutically acceptable salt and/or hydrate and/or prodrug of thecompound) that modulates (e.g., agonizes) the APJ receptor isadministered as a pharmaceutical composition that includes the chemicalentity and one or more pharmaceutically acceptable excipients, andoptionally one or more additional therapeutic agents as describedherein.

In some embodiments, the chemical entities can be administered incombination with one or more conventional pharmaceutical excipients.Pharmaceutically acceptable excipients include, but are not limited to,ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifyingdrug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol1000 succinate, surfactants used in pharmaceutical dosage forms such asTweens, poloxamers or other similar polymeric delivery matrices, serumproteins, such as human serum albumin, buffer substances such asphosphates, tris, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethyl cellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, andwool fat. Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemicallymodified derivatives such as hydroxyalkylcyclodextrins, including 2- and3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives canalso be used to enhance delivery of compounds described herein. Dosageforms or compositions containing a chemical entity as described hereinin the range of 0.005% to 100% with the balance made up from non-toxicexcipient may be prepared. The contemplated compositions may contain0.001%-100% of a chemical entity provided herein, in one embodiment0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%.Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington: TheScience and Practice of Pharmacy, 22^(nd) Edition (Pharmaceutical Press,London, U K. 2012).

Routes of Administration and Composition Components

In some embodiments, the chemical entities described herein or apharmaceutical composition thereof can be administered to subject inneed thereof by any accepted route of administration. Acceptable routesof administration include, but are not limited to, buccal, cutaneous,endocervical, endosinusial, endotracheal, enteral, epidural,interstitial, intra-abdominal, intra-arterial, intrabronchial,intrabursal, intracerebral, intracisternal, intracoronary, intradermal,intraductal, intraduodenal, intradural, intraepidermal, intraesophageal,intragastric, intragingival, intraileal, intralymphatic, intramedullary,intrameningeal, intramuscular, intraovarian, intraperitoneal,intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial,intratesticular, intrathecal, intratubular, intratumoral, intrauterine,intravascular, intravenous, nasal, nasogastric, oral, parenteral,percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous,sublingual, submucosal, topical, transdermal, transmucosal,transtracheal, ureteral, urethral and vaginal.

Compositions can be formulated for parenteral administration, e.g.,formulated for injection via the intravenous, intramuscular,sub-cutaneous, or even intraperitoneal routes. Typically, suchcompositions can be prepared as injectables, either as liquid solutionsor suspensions; solid forms suitable for use to prepare solutions orsuspensions upon the addition of a liquid prior to injection can also beprepared; and the preparations can also be emulsified. The preparationof such formulations will be known to those of skill in the art in lightof the present disclosure.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions; formulations including sesame oil,peanut oil, or aqueous propylene glycol; and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In general, the form must be sterile and must be fluid tothe extent that it may be easily injected. It also should be stableunder the conditions of manufacture and storage and must be preservedagainst the contaminating action of microorganisms, such as bacteria andfungi.

The carrier also can be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (for example, glycerol, propyleneglycol, and liquid polyethylene glycol, and the like), suitable mixturesthereof, and vegetable oils. The proper fluidity can be maintained, forexample, by the use of a coating, such as lecithin, by the maintenanceof the required particle size in the case of dispersion, and by the useof surfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like. In many cases, it will be preferable to include isotonicagents, for example, sugars or sodium chloride. Prolonged absorption ofthe injectable compositions can be brought about by the use in thecompositions of agents delaying absorption, for example, aluminummonostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompounds in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum-drying and freeze-dryingtechniques, which yield a powder of the active ingredient, plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Pharmacologically acceptable excipients usable in the rectal compositionas a gel, cream, enema, or rectal suppository, include, withoutlimitation, any one or more of cocoa butter glycerides, syntheticpolymers such as polyvinylpyrrolidone, PEG (like PEG ointments),glycerine, glycerinated gelatin, hydrogenated vegetable oils,poloxamers, mixtures of polyethylene glycols of various molecularweights and fatty acid esters of polyethylene glycol Vaseline, anhydrouslanolin, shark liver oil, sodium saccharinate, menthol, sweet almondoil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil,aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodiumpropyl p-oxybenzoate, diethylamine, carbomers, carbopol,methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate,isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum,carboxy-metabisulfite, sodium edetate, sodium benzoate, potassiummetabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM),lactic acid, glycine, vitamins, such as vitamin A and E and potassiumacetate.

In certain embodiments, suppositories can be prepared by mixing thechemical entities described herein with suitable non-irritatingexcipients or carriers such as cocoa butter, polyethylene glycol or asuppository wax which are solid at ambient temperature but liquid atbody temperature and therefore melt in the rectum and release the activecompound. In other embodiments, compositions for rectal administrationare in the form of an enema.

In other embodiments, the compounds described herein or a pharmaceuticalcomposition thereof are suitable for local delivery to the digestive orGI tract by way of oral administration (e.g., solid or liquid dosageforms).

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the chemicalentity is mixed with one or more pharmaceutically acceptable excipients,such as sodium citrate or dicalcium phosphate and/or: a) fillers orextenders such as starches, lactose, sucrose, glucose, mannitol, andsilicic acid, b) binders such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c)humectants such as glycerol, d) disintegrating agents such as agar-agar,calcium carbonate, potato or tapioca starch, alginic acid, certainsilicates, and sodium carbonate, e) solution retarding agents such asparaffin, f) absorption accelerators such as quaternary ammoniumcompounds, g) wetting agents such as, for example, cetyl alcohol andglycerol monostearate, h) absorbents such as kaolin and bentonite clay,and i) lubricants such as talc, calcium stearate, magnesium stearate,solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof.In the case of capsules, tablets and pills, the dosage form may alsocomprise buffering agents. Solid compositions of a similar type may alsobe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugar as well as high molecularweight polyethylene glycols and the like.

In one embodiment, the compositions will take the form of a unit dosageform such as a pill or tablet and thus the composition may contain,along with a chemical entity provided herein, a diluent such as lactose,sucrose, dicalcium phosphate, or the like; a lubricant such as magnesiumstearate or the like; and a binder such as starch, gum acacia,polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or thelike. In another solid dosage form, a powder, marume, solution orsuspension (e.g., in propylene carbonate, vegetable oils, PEG's,poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin orcellulose base capsule). Unit dosage forms in which one or more chemicalentities provided herein or additional active agents are physicallyseparated are also contemplated; e.g., capsules with granules (ortablets in a capsule) of each drug; two-layer tablets; two-compartmentgel caps, etc. Enteric coated or delayed release oral dosage forms arealso contemplated.

Other physiologically acceptable compounds include wetting agents,emulsifying agents, dispersing agents or preservatives that areparticularly useful for preventing the growth or action ofmicroorganisms. Various preservatives are well known and include, forexample, phenol and ascorbic acid.

In certain embodiments the excipients are sterile and generally free ofundesirable matter. These compositions can be sterilized byconventional, well-known sterilization techniques. For various oraldosage form excipients such as tablets and capsules, sterility is notrequired. The USP/NF standard is usually sufficient.

Ocular compositions can include, without limitation, one or more of anyof the following: viscogens (e.g., Carboxymethylcellulose, Glycerin,Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic(triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkoniumchloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zincchloride; Alcon Laboratories, Inc.), Purite (stabilized oxychlorocomplex; Allergan, Inc.)).

Topical compositions can include ointments and creams. Ointments aresemisolid preparations that are typically based on petrolatum or otherpetroleum derivatives. Creams containing the selected active agent aretypically viscous liquid or semisolid emulsions, often eitheroil-in-water or water-in-oil. Cream bases are typically water-washable,and contain an oil phase, an emulsifier and an aqueous phase. The oilphase, also sometimes called the “internal” phase, is generallycomprised of petrolatum and a fatty alcohol such as cetyl or stearylalcohol; the aqueous phase usually, although not necessarily, exceedsthe oil phase in volume, and generally contains a humectant. Theemulsifier in a cream formulation is generally a nonionic, anionic,cationic or amphoteric surfactant. As with other carriers or vehicles,an ointment base should be inert, stable, nonirritating andnon-sensitizing.

In any of the foregoing embodiments, pharmaceutical compositionsdescribed herein can include one or more one or more of the following:lipids, interbilayer crosslinked multilamellar vesicles, biodegradeablepoly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-basednanoparticles or microparticles, and nanoporous particle-supported lipidbilayers.

Dosages

The dosages may be varied depending on the requirement of the patient,the severity of the condition being treating and the particular compoundbeing employed. Proper dosage for a particular situation can bedetermined by one skilled in the medical arts. In some cases, the totaldaily dosage may be divided and administered in portions throughout theday or by means providing continuous delivery.

In some embodiments, the compounds described herein are administered ata dosage of from about 0.001 mg/Kg to about 500 mg/Kg (e.g., from about0.001 mg/Kg to about 200 mg/Kg; from about 0.01 mg/Kg to about 200mg/Kg; from about 0.01 mg/Kg to about 150 mg/Kg; from about 0.01 mg/Kgto about 100 mg/Kg; from about 0.01 mg/Kg to about 50 mg/Kg; from about0.01 mg/Kg to about 10 mg/Kg; from about 0.01 mg/Kg to about 5 mg/Kg;from about 0.01 mg/Kg to about 1 mg/Kg; from about 0.01 mg/Kg to about0.5 mg/Kg; from about 0.01 mg/Kg to about 0.1 mg/Kg; from about 0.1mg/Kg to about 200 mg/Kg; from about 0.1 mg/Kg to about 150 mg/Kg; fromabout 0.1 mg/Kg to about 100 mg/Kg; from about 0.1 mg/Kg to about 50mg/Kg; from about 0.1 mg/Kg to about 10 mg/Kg; from about 0.1 mg/Kg toabout 5 mg/Kg; from about 0.1 mg/Kg to about 1 mg/Kg; from about 0.1mg/Kg to about 0.5 mg/Kg).

Regimens

The foregoing dosages can be administered on a daily basis (e.g., as asingle dose or as two or more divided doses) or non-daily basis (e.g.,every other day, every two days, every three days, once weekly, twiceweeks, once every two weeks, once a month).

In some embodiments, the period of administration of a compounddescribed herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks,11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9months, 10 months, 11 months, 12 months, or more. In a furtherembodiment, a period of during which administration is stopped is for 1day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11months, 12 months, or more. In an embodiment, a therapeutic compound isadministered to an individual for a period of time followed by aseparate period of time. In another embodiment, a therapeutic compoundis administered for a first period and a second period following thefirst period, with administration stopped during the second period,followed by a third period where administration of the therapeuticcompound is started and then a fourth period following the third periodwhere administration is stopped. In an aspect of this embodiment, theperiod of administration of a therapeutic compound followed by a periodwhere administration is stopped is repeated for a determined orundetermined period of time. In a further embodiment, a period ofadministration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks,11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9months, 10 months, 11 months, 12 months, or more. In a furtherembodiment, a period of during which administration is stopped is for 1day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11months, 12 months, or more.

Methods of Treatment

This disclosure features methods for treating a subject (e.g., a human)having a disease, disorder, or condition in which a decrease in APJreceptor activity (e.g., repressed or impaired APJ receptor signaling;e.g., repressed or impaired apelin-APJ receptor signaling) ordownregulation of endogenous apelin contributes to the pathology and/orsymptoms and/or progression of the disease, disorder, or condition. Incertain embodiments, the methods described herein can include or furtherinclude treating one or more conditions associated, co-morbid or sequelawith any one or more of the conditions described herein.

In some embodiments, the method further comprises identifying thesubject. In some embodiments, identifying comprises determining thelevel of one or more of the following parameters in the subject:leukotriene B4 level, pulmonary vascular resistance, pulmonary arterialpressure, cardiac index, pulmonary capillary wedge pressure, rightatrial pressure, six-minute walk distance, brain natriuretic peptidelevel, atrial natriuretic peptide, and diffusion of lung capacity.

In certain embodiments, the chemical entities described herein modulate(e.g., decrease) pulmonary vascular resistance, modulate (e.g.,decrease) right ventricular afterload, and modulate (e.g., decrease)mean pulmonary artery pressure. In certain embodiments, the chemicalentities described herein reduce the risk of right ventricular failure.

In certain embodiments, the chemical entities described herein modulatevascular tone, modulate fluid homeostasis, modulate kidney function,modulate energy metabolism, modulate inflammatory response, and modulatethrombosis.

Indications

Pulmonary Hypertension

In some embodiments, the condition, disease or disorder is pulmonaryarterial hypertension (PAH). Non-limiting examples of PAH and relatedconditions include idiopathic PAH, heritable PAH (e.g., BMPR2 mutationsand other mutations), drug-induced or toxin-induced PAH, and PAHassociated with conditions including but not limited to connectivetissue diseases (CTD) (e.g., scleroderma, systemic lupus erythematosus,systemic sclerosis, Hashimoto's thyroiditis, Sjogren's Syndrome, and theantiphospholipid antibody syndrome), HIV infection, portal hypertension,congenital heart disease, and schistosomiasis.

In some embodiments, the PAH is idiopathic.

In other embodiments, the PAH is heritable PAH, toxin or drug-inducedPAH; or a PAH associated with one or more of the following: congenitalheart disease, connective tissue disorders (e.g., scleroderma, systemiclupus erythematosus, systemic sclerosis, Hashimoto's thyroiditis,Sjogren's Syndrome, and the antiphospholipid antibody syndrome), portalhypertension, BMPR2 mutations, Schistosomiasis, and HIV infection.

In some embodiments, the condition, disease or disorder is pulmonaryhypertension other than PAM. Examples of such conditions include,without limitation, pulmonary hypertension due to left heart disease(e.g., left ventricular systolic dysfunction, left ventricular diastolicdysfunction, valvular heart disease, and congenital/acquired left heartinflow/outflow obstruction and congenital cardiomyopathies), pulmonaryhypertension due to lung disease and/or hypoxia (e.g., choronicobstructive pulmonary disease, interstitial lung disease, otherpulmonary disease with mixed restrictive and obstructive pattern,sleep-disordered breathing, alveolar hypoventilation disorders, chronicexposure to high altitude, developmental lung disease), chronicthromboembolic pulmonary hypertension and other pulmonary arteryobstructions (e.g., chronic thromboembolic pulmonary hypertension, otherpulmonary artery obstructions), and pulmonary hypertension with unclearmultifactorial mechanisms (e.g., haematologic disorders, systemicdisorders, metabolic disorders, and others).

Cardiovascular Conditions, Diseases or Disorders

In some embodiments, the condition, disease or disorder is acardiovascular condition, disease or disorder. Non-limiting examples ofcardiovascular condition, disease or disorder include coronary heartdisease, acute coronary syndrome, peripheral vascular disease, angina,stroke, cerebrovascular accidents, transient ischemic attacks, heartfailure, cardiomyopathy, myocardial infarction, myocardial remodelingafter cardiac surgery, valvular heart disease, hypertension (e.g.,systemic hypertension, essential hypertension, pulmonary hypertension,portal hypertension, systolic hypertension), aortic aneurysm (e.g.,abdominal aortic aneurysm), atrial fibrillation, arrhythmia,atherosclerosis, Brugada syndrome, ischemic cardiovascular diseases,peripheral arterial disease, preeclampsia, ventricular tachycardia, andcardiac fibrosis.

In some embodiments, the cardiovascular condition, disease or disorderis heart failure. Non-limiting examples of heart failure include chronicheart failure, systolic heart failure, diastolic heart failure, diabeticheart failure, congestive heart failure, heart failure with preservedejection fraction, heart failure with reduced ejection fraction, leftventricular dysfunction (e.g., left ventricular dysfunction aftermyocardial infarction), right ventricular dysfunction, cardiachypertrophy, myocardial remodeling, and acute decompensated heartfailure (ADHF).

In some embodiments, the cardiovascular condition, disease or disorderis a condition, disease or disorder with vascular pathology (e.g., withincreased vascular permeability and nonfunctional blood vessels).Non-limiting examples of such condition, disease or disorder includevascular hypertrophy, vascular remodeling (e.g., vascular stiffness),atherosclerosis, peripheral arterial occlusive disease (PAOD),restenosis (e.g., angioplastic restenosis), thrombosis and vascularpermeability disorders, and ischemia and/or reperfusion damage (e.g.,ischemia and/or reperfusion damage of the heart, kidney and retina). Insome embodiments, the conditions, disease or disorder is vein related.Non-limiting examples of such condition, disease or disorder includeangioma, veinous insufficiency, stasis, or thrombosis.

In some embodiments, the chemical entities described herein can improvecardiac contractility (e.g., cardiac relaxation), ventricular arterialcoupling, inotropic function, or luistropic function in a subjectsuffering from a cardiovascular condition. In some embodiments, thechemical entities described herein can increase ejection fraction in asubject suffering from a cardiovascular condition.

Metabolic and Homeostatic Dysfunction and Related Conditions, Diseasesor Disorders

In some embodiments, the condition, disease or disorder is associatedwith metabolic dysfunction. Non-limiting examples of such condition,disease or disorder include metabolic dysfunction, obesity, diabetes(e.g., type II diabetes mellitus, gestational diabetes), complicationsof diabetes (e.g., metabolic syndrome, insulin resistance, organ damagesof micro- or macrovascular origins such as macro- andmicrovaculopathies, diabetic neuropathy, diabetic retinopathy, cardiacautonomic neuropathy), kidney disease (e.g., chronic kidney disease),edema, dyslipidemia, anorexia, hyperphagia, polyphagia,hypercholesterolemia, hyperglyceridemia, hyperlipemia, growth hormonedisorder (e.g., gigantism, aromegaly), galactorrhea, and cardiacwasting.

In some embodiments, the condition, disease or disorder is associatedwith inappropriate vasopressin secretions (SIADH). Non-limiting examplesof such condition, disease or disorder include neurogenic diabetesmellitus (e.g. diabetic complications such as diabetic nephropathy,diabetic neuropathy, diabetic retinopathy, etc.), lung cancer, septicshock, and thirst troubles.

In some embodiments, the condition, disease or disorder is associatedwith systemic inflammation. Non-limiting examples of such condition,disease or disorder include systemic inflammatory response syndrome(SIRs), sepsis (e.g., severe sepsis), and septic shock. In someembodiments, the condition, disease or disorder is associated withsepsis (e.g., a complication, co-morbidity, or sequela of sepsis).Non-limiting examples of conditions, diseases or disorders associatedwith sepsis include sepsis-induced myocardial dysfunction,sepsis-related inflammatory response (e.g., systemic inflammation),sepsis-related hemodynamic alterations, hypovolemia, sepsis-relatedorgan failures (e.g., multi-organ failure, renal failure), acute kidneyinjury, vasoplegia, lung injury, inappropriate vasopressin secretions,persistent hypertension related to generalized vasodilation, refractoryconstrictive responsiveness, huge plasma capillary leak syndrome,coagulation/fibrinolysis imbalance, and metabolic disturbancehighlighted by elevated blood-stream lactates. See. e.g., Coquerel etal. Critical Care (2018) 22:10.

In some embodiments, the chemical entities described herein can regulatearginine vasopressin (AVP) or angiotensin receptor.

In some embodiments, the condition, disease or disorder is associatedwith disturbed body's fluid homeostasis by CNS-dependent and-independent effects. Non-limiting examples of such condition, diseaseor disorder include renal failure (e.g., acute and chronic renalfailure), renal perfusion, renal dysfunction (e.g., polycystic kidneydisease), aquaresis, and diuresis.

Dementia and Related Conditions, Diseases or Disorders

In some embodiments, the condition, disease or disorder is dementia.Non-limiting examples of such condition, disease or disorder includesenile dementia, cerebrovascular dementia, dementia due to genealogicaldenaturation degenerative diseases (e.g. Alzheimer's disease,Parkinson's disease, Pick's disease, Huntington's disease, etc.),dementia resulting from infectious diseases (e.g. delayed virusinfections such as Creutzfeldt-Jakob disease), dementia associated withendocrine diseases, metabolic diseases, or poisoning (e.g.hypothyroidism, vitamin B12 deficiency, alcoholism, poisoning caused byvarious drugs, metals, or organic compounds), dementia caused by tumors(e.g. brain tumor), and dementia due to traumatic diseases (e.g. chronicsubdural hematoma), depression, hyperactive child syndrome(microencephalopathy), disturbance of consciousness, anxiety disorder,schizophrenia, and phobia.

Connective Tissue Disorder

In some embodiments, the condition, disease or disorder is a connectivetissue disorder. In certain embodiments, the connective tissue disorderis selected from the group consisting of: scleroderma, systemic lupuserythematosus, systemic sclerosis, Hashimoto's thyroiditis, Sjogren'sSyndrome, and the antiphospholipid antibody syndrome. In certainembodiments, the condition, disease or disorder is systemic sclerosis.

Fibrosis

In some embodiments, the condition, disease or disorder is fibrosis. Incertain embodiments, the fibrosis is associated with an organ or tissueselected from the group consisting of: lung, liver, heart, mediastinum,bone marrow, retroperitoneaum, skin, intestine, joint, a reproductiveorgan, and a combination thereof. In certain embodiments, the fibrosisis idiopathic pulmonary fibrosis (IPF). In certain embodiments, thefibrosis is liver fibrosis. In certain embodiments, the fibrosis isassociated with non-alcoholic fatty liver disease (NAFLD)

Other Conditions, Diseases or Disorders

In some embodiments, the condition, disease or disorder is a liverdisease. Non-limiting examples of such condition, disease or disorderinclude alcoholic liver disease, toxicant-induced liver disease, viralinduced liver disease, and liver cirrhosis.

In some embodiments, the condition, disease or disorder is a pulmonarydisease. Non-limiting examples of such condition, disease or disorderinclude chronic obstructive pulmonary disease (COPD), asthma, acuterespiratory dystress syndrome (ARDS), and amyotrophiclateral sclerosis.In some embodiments, the condition, disease or disorder is a retinaldisease (e.g., macular degeneration).

In some embodiments, the condition, disease or disorder is HIVinfection, HIV neurodegeneration, neurodegenerative disease, cancer(e.g., mammary cancer, lymphocytic leukemia, bladder cancer, ovarycancer, carcinoma of prostate, etc.), asthma, burn injuries (e.g., sunburn), traumatic brain injuries, pancreatitis, Turner's syndrome,neurosis, rheumatoid arthritis, spinal cord injury, immune function,inflammation, spinocerebellar degeneration, bone fracture, wounds,atopic dermatitis, osteoporosis, asthma, epilepsy, and sterility.

Activating Stem Cells

The chemical entities described herein can also be used to activate stemcells (e.g., cardiac stem cells such as endogenous cardiac stem cells).In some embodiments, the chemical entities described herein can be usedin regrowing tissue, assisting functional recovery after transplantingcells (e.g., cells with bone marrow-derived mesenchymal stem cells),increasing cardiac stem cell proliferation (e.g., in patents that havesuffered a myocardial infarction), reducing infarct size, promotingcardiac repair, activating stem cells and progenitors in postmyocardialinfarction subjects, or reducing reperfusion injury (e.g., duringsurgeries such as heart bypass surgery or heart transplant procedures).

Combination Therapy

This disclosure contemplates both monotherapy regimens as well ascombination therapy regimens.

In some embodiments, the methods described herein can further includeadministering one or more additional therapies (e.g., one or moreadditional therapeutic agents and/or one or more therapeutic regimens)in combination with administration of the compounds described herein.

In some embodiments, the compound described herein can be administeredin combination with one or more of additional therapeutic agents.

Representative additional therapeutic agents include, but are notlimited to, therapeutic agents for PAH, pulmonary hypertension, heartfailure (e.g., ADHF, chronic heart failure), hypertension (e.g.,systemic hypertension), amyotrophic lateral sclerosis, arrhythmia,asthma, atherosclerosis, atrial fibrillation, Brugada syndrome, burninjuries (e.g., sunburn), cancer, cardiac fibrosis, cardiomyopathy,cerebrovascular accidents, diabetes (e.g., gestational diabetes), septicshock, sepsis, renal failure, dyslipidemia, HIV neurodegeneration,inflammation, ischemic cardiovascular disease, liver disease, metabolicdisorder, neurodegenerative disease, obesity, peripheral arterialdisease, preeclampsia, restenosis, transient ischemic attacks, traumaticbrain injuries, ventricular tachycardia, edema, or immune function.

In some embodiments, the one or more additional therapeutic agentsinclude those useful, e.g., as therapeutics for PAH. Non-limitingexamples include:

-   -   prostacyclin analogues (e.g., Epoprostenol, Treprostinil,        Iloprost);    -   prostacyclin IP receptor (e.g., Selexipag);    -   endothelin receptor antagonists (e.g., Bosentan, Ambrisentan,        Macitentan);    -   PDE 5 inhibitors (e.g., Sildenafil, Tadalafil);    -   soluble guanylate cyclase stimulator (e.g., Riociguat);    -   therapeutics for mitochondria dysfunction (e.g., Bardoxolone        methyl);    -   anti-inflammation agents (e.g., Rituximab, Tocilizumab,        Ubenimex); and    -   agents that modulate oxidative stress (e.g., dimethyl fumarate,        intravenous iron).

In some embodiments, the one or more additional therapeutic agentsinclude those useful, e.g., as therapeutics for heart failure orhypertension. Non-limiting examples include:

-   -   α-blockers (e.g., doxazosin, prazosin, tamsulosin, terazosin);    -   β-blockers (e.g., acebutolol, acetutolol, atenolol, bisoprol,        bupranolol, carteolol, carvedilol, celiprolol, esmolol,        mepindolol, metoprolol, nadolol, oxprenolol, penbutolol,        pindolol, propranolol, taliprolol);    -   calcium channel blockers including but not limited to        dihydropyridines (DHPs) (e.g., amlodipine, felodipine,        isradipine, lacidipine, nicardipine, nifedipine, nigulpidine,        nilutipine, nimodiphine, nisoldipine, nitrendipine, nivaldipine,        ryosidine) and non-DHPs (e.g., anipamil, diltiazem, fendiline,        flunarizine, gallpamil, mibefradil, prenylamine, tiapamil,        verapamil);    -   diurectics (e.g., thiazide derivatives such as, but not limited        to, amiloride, chlorothalidon, chlorothiazide,        hydrochlorthiazide, and methylchlorothiazide)    -   centrally acting hypertensive agents (e.g., clonidine,        guanabenz, guanfacine, methyldopa);    -   angiotensin converting enzyme (ACE) inhibitors (alaceptril,        benazepril, benazaprilat, captopril, ceronapril, cilazapril,        delapril, enalapril, analaprilat, fosinopril, Lisinopril,        moexipiril, moveltopril, perindopril, quinapril, quinaprilat,        ramipril, ramiprilat, spriapril, temocapril, trendolapril, and        zofenopril) and dual ACE/NEP inhibitors (e.g., omapatrilat,        fasidotril, and fasidotrilat);    -   angiotensin receptor blockers (ARBs) (e.g., candesartan,        eprosartan, irbesartan, losartan, olmesartan, tasosartan,        telmisartan, valsartan) and dual ARB/NEP inhibitors (e.g.,        combinations of valsartan and sacubitril);    -   neutral endopeptidase (NEP) inhibitor (e.g., sacubitril);    -   aldosterone synthase inhibitors (e.g., anastrozole, fadrozole,        exemestane);    -   endothelin antagonists (e.g., bosentan, enrasentan, atrasentan,        darusentan, macitentan, sitaxentan, tezosentan);    -   inhibitors of funny current (e.g., ivabradine);    -   myosin activators (e.g., cardiac myosin activators);    -   natriuretic;    -   saluretic;    -   vasodilator/vasorelaxation agents (e.g., nitrates)    -   mineralocorticoid receptor antagonists;    -   renin inhibitors;    -   digitalis compounds;    -   inotropic agents and β-receptor agonists;    -   anti-hyperlipidemic agents;    -   plasma HDL-raising agents;    -   anti-hypercholesterolemic agents;    -   cholesterol biosynthesis inhibitors (e.g., HMG CoA reductase        inhibitors) LXR agonist;    -   probucol;    -   raloxifene;    -   nicotinic acid;    -   niacinamide;    -   cholesterol absorption inhibitors;    -   bile acid sequestrants (e.g., anion exchange resins, or        quaternary amines such as cholestyramine or colestipol);    -   low density lipoprotein receptor inducers;    -   clofibrate;    -   fenofibrate;    -   bezafibrate;    -   ciprofibrate;    -   gemfibrizol;    -   vitamins (e.g., vitamin B₆, vitamin B₁₂, anti-oxidant vitamins);    -   platelet aggregation inhibitors;    -   fibrinogen receptor antagonists;    -   aspirin; and    -   fibric acid derivatives.

In some embodiments, the one or more additional therapeutic agentsinclude those useful, e.g., for treating diabetes. Non-limiting examplesinclude:

-   -   sulfonylureas (e.g., chlorpropamide, tolbutamide, acetohexamide,        tolazamide, glyburide, gliclazide, glynase, glimepiride,        glipizide);    -   biguanides (e.g., metformin);    -   thiazolidinediones (e.g., ciglitazone, pioglitazone,        troglitazone, rosiglitazone)    -   insulin sensitizers related to the above (e.g., selective and        non-selective activators of PPAR-alpha, PPAR-beta and        PPAR-gamma);    -   dehydroepiandrosterone (also referred to as DHEA or its        conjugated sulfate ester, DHEA-SO₄);    -   anti-glucocorticoids;    -   TNF-alpha inhibitors;    -   dipeptidyl peptidase IV (DPP4) inhibitors (e.g.; sitagliptin,        saxagliptin);    -   GLP-1 agonists or analogs (such as exenatide);    -   alpha-glucosidase inhibitors (such as acarbose, miglitol, and        voglibose);    -   pramlintide (a synthetic analog of the human hormone amylin);    -   other insulin secretagogues (such as repaglinide, gliquidone,        and nateglinide); and    -   insulin.

In some embodiments, the one or more additional therapeutic agentsinclude those useful, e.g., for treating obesity. Non-limiting examplesinclude phenylpropanolamine, phentermine, diethylpropion, mazindol,fenfluramine, dexfenfluramine, phentiramine, beta3-adrenergic receptoragonist agents, sibutramine, gastrointestinal lipase inhibitors (e.g.,orlistat), leptins, neuropeptide Y, enterostatin, cholecytokinin,bombesin, amylin, histamine H₃ receptors, dopamine D₂ receptormodulators, melanocyte stimulating hormone, corticotrophin releasingfactor, galanin, and gamma amino butyric acid (GABA).

Other additional therapeutic agents include:

-   -   anti-atherosclerotic agents;    -   anti-dyslipidemic agents;    -   antihyperinsulinemic agents;    -   anti-thrombotic agents;    -   anti-retinopathic agents;    -   anti-neuropathic agents;    -   anti-nephropathic agents;    -   anti-ischemic agents;    -   anti-hyperlipidemic agents;    -   anti-hypertriglyceridemic agents;    -   anti-hypercholesterolemic agents;    -   anti-restenotic-agents;    -   anti-pancreatic agents;    -   anorectic agents;    -   memory enhancing agents;    -   antidementia agents;    -   cognition promoting agents;    -   appetite suppressants;    -   agents for treating peripheral arterial disease;    -   agents for treating malignant tumors;    -   anti-innammatory agents;    -   aquaretics;    -   digoxin;    -   nitric oxide donors;    -   hydralazines;    -   a ionotropes;    -   vasopressin receptor antagonists;    -   statins;    -   anti-arrhythmics;    -   phosphodiesterase inhibitors (e.g., PDE5 inhibitors); and    -   nephro-protectives.

Non-limiting examples of additional therapeutic agents can also includethose described in U.S. Pat. No. 9,156,796B2, which is incorporatedherein by reference.

In certain embodiments, the second therapeutic agent or regimen isadministered to the subject prior to contacting with or administeringthe chemical entity (e.g., about one hour prior, or about 6 hours prior,or about 12 hours prior, or about 24 hours prior, or about 48 hoursprior, or about 1 week prior, or about 1 month prior).

In other embodiments, the second therapeutic agent or regimen isadministered to the subject at about the same time as contacting with oradministering the chemical entity. By way of example, the secondtherapeutic agent or regimen and the chemical entity are provided to thesubject simultaneously in the same dosage form. As another example, thesecond therapeutic agent or regimen and the chemical entity are providedto the subject concurrently in separate dosage forms.

In still other embodiments, the second therapeutic agent or regimen isadministered to the subject after contacting with or administering thechemical entity (e.g., about one hour after, or about 6 hours after, orabout 12 hours after, or about 24 hours after, or about 48 hours after,or about 1 week after, or about 1 month after).

Compound Preparation and Biological Assays

As can be appreciated by the skilled artisan, methods of synthesizingthe compounds of the formulae herein will be evident to those ofordinary skill in the art. Synthetic chemistry transformations andprotecting group methodologies (protection and deprotection) useful insynthesizing the compounds described herein are known in the art andinclude, for example, those such as described in R. Larock,Comprehensive Organic Transformations, VCH Publishers (1989); T. W.Greene and RGM. Wuts, Protective Groups in Organic Synthesis, 2d. Ed.,John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser'sReagents for Organic Synthesis, John Wiley and Sons (1994); and L.Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, JohnWiley and Sons (1995), and subsequent editions thereof.

In some embodiments, intermediates useful for preparing the compoundsdescribed herein can be prepared using the chemistries delineated in anyone or more of the following schemes and non-limiting examples.

Compound Preparation

For illustrative purposes, Schemes 1-4 show general methods forpreparing the compounds provided herein as well as intermediates. For amore detailed description of the individual reaction steps, see theSynthetic Examples section below. Those skilled in the art willappreciate that other synthetic routes may be used to synthesize theinventive compounds. Although specific starting materials and reagentsare depicted in the Scheme and discussed below, other starting materialsand reagents can be easily substituted to provide a variety ofderivatives and/or reaction conditions. In addition, many of thecompounds prepared by the methods described below can be furthermodified in light of this disclosure using conventional chemistry wellknown to those skilled in the art.

Referring to Scheme 1, a compound of Formula (I) (shown as I-6 and I-7)may be prepared from compound I-1, I-2, and I-4 wherein R¹ and R² are asdefined herein. Aminopyrazine I-1 can be reacted with carboxylic acidI-2 to afford amide I-3 (wherein X is a halo such as bromo or chloro)under standard conditions (e.g., in the presence of oxalyl chloridewhich converts I-2 into an acyl chloride or in the presence of peptidecoupling reagents). Then a reaction under S_(N)Ar or metal catalyzedcross-coupling conditions (e.g., Buchwald Hartwig coupling usingXantphos and Pd(OAc)₂) between I-3 and amine I-4 can provide compoundI-5. Condensation of the carbonyl moiety in I-5 onto the amino group canprovide I-6, a compound of Formula (I).

Alternatively, I-3 may be obtained through the coupling between I-1 andan ester of I-2 (e.g., alkyl ester, e.g., methyl or ethyl ester) underappropriate conditions (e.g., in the presence of AlMe₃).

Optionally, the X moiety in I-6 can be converted into other R³ groups toprovide I-7, another compound of Formula (I). As non-limiting examplesfor the transformation between I-6 and I-7, I-6 can be reacted with asulfonamide under Ullmann coupling conditions to provide compound I-8(vide supra, Scheme 1).

The following starting materials can be used in place of I-1 andsubjected to the sequence depicted in Scheme 1.

Referring to Scheme 2, a compound of Formula (I) (shown as compoundsII-7 to II-9) in Scheme 2 may be prepared from compound II-1 wherein R¹is as defined elsewhere herein, and X is a halo (e.g., Br) or pseudohalo(e.g., OTf) group. II-1 can be subjected to a Sonogashira coupling orequivalent thereof with a protected acetylene (e.g., TMS-acetylene) toprovide compound II-2. Subsequent removal of the alkyne protecting groupcan afford II-3 which can be coupled with pyrazine derivative II-4 tofurnish compound II-5. Cyclization of the amino group in II-5 onto thealkynyl moiety can result in compound II-6, which can be subjected tocross-coupling with a boronic acid of the formula R²—B(OH)₂ wherein R²is as defined elsewhere herein or a boronate ester thereof (e.g., underChan-Lam coupling conditions) to afford compound II-7, which is acompound of Formula (I). Compound II-7 can be further functionalizedprovide compound II-8, also a compound of Formula (I).

As an non-limiting example for the transformation of II-7 to II-8, II-7can be coupled with a compound of formula H₂NS(O)₂R⁴ wherein R⁴ is asdefined elsewhere herein (e.g., under Ullmann coupling conditions) toafford compound II-9, a non-limiting example of compound II-8.

Referring to Scheme 3, a compound of Formula (I) (shown as compoundsIII-5 to III-7 in Scheme 3) may be prepared from compound III-1 whereinR¹ is as defined elsewhere herein. Coupling between III-1 and III-2(e.g., in the presence of a Lewis acid such as AlMe₃) can providecompound III-3, which can be subjected to cross-coupling with a compoundof formula R²NH₂ wherein R² is as defined elsewhere herein to affordcompound III-4. Cyclization of the amino group in III-4 onto the amidemoiety (e.g., in the presence of P(O)Cl₃ under heat) can provide III-5,which is a compound of Formula (I). III-5 can functionalized to provideIII-6, also a compound of Formula (I).

As an non-limiting example for the transformation of III-5 to III-6,II-5 can be coupled with a compound of formula H₂NS(O)₂R⁴ wherein R⁴ isas defined elsewhere herein (e.g., under Ullmann coupling conditions) toafford compound III-7, a non-limiting example of compound III-6.

Referring to Scheme 4, a compound of Formula (I) (shown as compoundsIV-6 to IV-8 in Scheme 4) may be prepared from pyridazine derivativeIV-1. Sequential treatment of IV-1 with ammonium hydroxide and brominecan provide IV-3, whereupon the coupling of IV-3 and R¹CO₂H (wherein R¹is as defined elsewhere herein) can provide IV-4. IV-4 can be subjectedto coupling with R²NH₂ wherein R² is as defined elsewhere herein (e.g.,under Buchwald-Hartwig coupling conditions) to provide IV-5 which canundergo cyclization (e.g., under heat and/or microwave irradiation) toafford IV-6, a compound of Formula (I). Compound IV-6 may befunctionalized to provide IV-7, also a compound of Formula (I).

As an non-limiting example for the transformation of IV-6 to IV-7, IV-6can be coupled with a compound of formula H₂NS(O)₂R⁴ wherein R⁴ is asdefined elsewhere herein (e.g., under Ullmann coupling conditions) toafford compound IV-8, a non-limiting example of compound IV-7.

Referring to Scheme 5, a compound of Formula (I) (shown as V-6 and V-7)may be prepared from compound V-1, V-2, and V-4 wherein R¹ and R² are asdefined herein. Aminopyrazine V-1 can be reacted with carboxylic acidV-2 to afford amide V-3 (wherein X is a halo such as bromo orchloro)under standard conditions. Then a reaction under S_(N)Ar or metalcatalyzed cross-coupling conditions (e.g., Buchwald Hartwig couplingusing Xantphos and Pd(OAc)₂) between V-3 and amine V-4 can providecompound V-5. Condensation of the carbonyl moiety in V-5 onto the aminogroup can provide V-6, a compound of Formula (I).

Alternatively, V-3 may be obtained through the coupling between V-1 andan ester of V-2 (e.g., alkyl ester, e.g., methyl or ethyl ester) underappropriate conditions (e.g., in the presence of AlMe₃).

Optionally, the X moiety in V-6 can be converted into other R³ groups toprovide I-7, another compound of Formula (I). As non-limiting examplesfor the transformation between V-6 and V-7, V-6 can be reacted with asulfonamide under Ullmann coupling conditions to provide compound V-8(vide supra, Scheme 5).

General Procedures

Reactions sensitive to moisture or air were performed under nitrogen orargon using anhydrous solvents and reagents. The progress of reactionswas determined by either analytical thin layer chromatography (TLC)usually performed with Sanpont precoated TLC plates, silica gel GF-254,layer thickness 0.25 mm or liquid chromatography-mass spectrometry(LC-MS).

Typically the analytical LC-MS system used consisted of an Agilent 6120platform with electrospray ionization in positive ion detection modewith an Agilent 1260 series HPLC with autosampler. The column wasusually an Agilent poroshell C18, 3.0×50 mm, 2.7 μm. The flow rate was0.6 mL/min, and the injection volume was 5 μL. UV detection was in therange 190-400 nm. The mobile phase consisted of solvent A (water plus0.1% TFA) and solvent B (acetonitrile plus 0.05% TFA) with a gradient of90% solvent A changing to 95% solvent B over 1.7 min, maintained for 1.8min, then reverting to 90% solvent A over 0.1 min and maintained for 1.4mins.

Preparative HPLC purifications were usually performed Waters 2555-2767system with a 2489 UV detector. The column was Welch C-18, 21.2×150 mm,5 μm. The mobile phases consisted of mixtures of acetonitrile (5-95%) inwater containing 0.05% TFA. Flow rates were maintained at 20 mL/min, theinjection volume was 1800 μL, and the UV detector used two channels 254nm and 280 nm. Mobile phase gradients were optimized for the individualcompounds.

Reactions performed using microwave irradiation were normally carriedout using an Initiator manufactured by Biotage. Concentration ofsolutions was carried out on a rotary evaporator under reduced pressure.Flash chromatography was usually performed using a Biotage FlashChromatography apparatus (Dyax Corp.) on silica gel (40-63 mM, 60 Å poresize) in pre-packed cartridges of the size noted. ¹H NMR spectra wereacquired at 400 MHz spectrometers in CDCl₃ solutions unless otherwisenoted. Chemical shifts were reported in parts per million (ppm).Tetramethylsilane (TMS) was used as internal reference in CD₃Clsolutions, and residual CH₃OH peak or TMS was used as internal referencein CD₃OD solutions. Coupling constants (J) were reported in hertz (Hz).Chiral analytical chromatography was performed on one of Chiralpak AS,Chiralpak AD, Chiralcel OD, Chiralcel IA, or Chiralcel OJ columns(250×4.6 mm) (Daicel Chemical Industries, Ltd.) with noted percentage ofeither ethanol in hexane (% Et/Hex) or isopropanol in heptane (%IPA/Hep) as isocratic solvent systems. Chiral preparative chromatographywas conducted on one of Chiralpak AS, Chiralpak AD, Chiralcel OD,Ciralcel IA, or Chiralcel OJ columns (20×250 mm) (Daicel ChemicalIndustries, Ltd.) with desired isocratic solvent systems identified onchiral analytical chromatography or by supercritical fluid (SFC)conditions.

ABBREVIATIONS

—C(O)CH₃ (Ac); acetic acid (AcOH); —OC(O)CH₃ (OAc); aqueous (aq); Cbz(benzyloxycarbonyl); N,N-diisopropylethylamine (DIEA);N;N-dimethylformamide (DMF);1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI); ethyl acetate(EtOAc); diethyl ether (ether or Et₂O); petroleum ether (PE); gram(s)(g); hour(s) (h or hr); 2-propanol (IPA); mass spectrum (ms or MS);microliter(s) (μL); milligram(s) (mg); milliliter(s) (mL); millimole(mmol); minute(s) (min); methyl t-butylether (MTBE);(benzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate(PyBOP); retention time (R_(t)); room temperature (rt or RT); saturatedaq sodium chloride solution (brine); trifluoroacetic acid (TFA);tetrahydrofuran (THF); flash chromatography (FC); liquid chromatography(LC); liquid chromatography-mass spectrometry (LCMS or LC-MS);supercritical fluid chromatography (SFC); t-butyloxycarbonyl (Boc orBOC); Diethylaminosulfur trifluoride (DAST); dichloromethane (DCM);dimethylacetamide (DMA; DMAC); dimethylsulfoxide (DMSO);1,3-Bis(diphenylphosphino)propane (DPPP); acetic acid (HOAc);3-chloroperoxybenzoic acid (m-CPBA); methyl (Me); methanol (MeOH);N-bromosuccinamide (NBS); thin layer chromatography (TLC).

SYNTHETIC EXAMPLES

The following are representative procedures for the preparation of thecompounds used in the following Examples, or which can be substitutedfor the compounds used in the following Examples which may not becommercially available.

Example 1:6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine

And

Example 2:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

Step A: ethyl 6-ethoxypicolinate

Ethyl iodide (112.2 g, 720 mmol, 4 equiv) was added to a suspension of6-hydroxy-pyridine-2-carboxylic acid (25.0 g, 180 mmol, 1 equiv) andsilver(I) carbonate (100 g, 360 mmol, 2 equiv) in CHCl₃ (400 mL). Themixture was stirred at 30° C. for 1 day. Insoluble material was removedby filtration and the solid was washed with CHCl₃. The filtrate wasconcentrated in vacuo to afford the title compound ethyl6-ethoxypicolinate as light yellow oil which was used in the next stepwithout further purification.

LC-MS: m/z 196.0 (M+H)⁺

Step B: 6-ethoxypicolinic acid

To a solution of ethyl 6-ethoxypicolinate (25 g, 128 mmol, 1 equiv) inEtOH (30 mL) was added sodium hydroxide solution (1 mol/L, 384 mL, 384mmol, 3 equiv). The reaction mixture was stirred at room temperature for3 hours. The reaction mixture was neutralized with 1 N HCl (aq.)solution and extracted with ethyl acetate. The extract was washed withbrine, dried over MgSO₄ and concentrated in vacuo to afford the titlecompound 6-ethoxypicolinic acid.

LC-MS: m/z 168.0 (M+H)⁺

Step C: N-(3,5-dibromopyrazine-2-yl)-6-ethoxypicolinamide

A solution of 6-ethoxypicolinic acid (10 g, 59.9 mmol, 1 equiv) in DCM(100 mL) was added oxalyl chloride (11.4 g, 89.8 mmol, 1.5 equiv) andDMF (1 mL) dropwise at 0° C. The resulted mixture was stirred at roomtemperature for 1 hour. The reaction solution was concentrated to affordthe crude 6-ethoxypicolinic chloride as a light yellow solid. Asuspension of 3,5-dibromopyrazin-2-amine (14.4 g, 56.9 mmol, 0.95 equiv)and NaH (6.8 g, 170.7 mmol, 2.85 equiv) in DMF (100 mL) was stirred atroom temperature for 1 hour. Then the crude 6-ethoxypicolinic chloridein DMF (100 mL) was added dropwise over a period of 30 min. After theaddition, the mixture was stirred at room temperature overnight. Themixture was quenched with saturated NH₄Cl (aq.) (100 mL) and extractedwith DCM (3*150 mL). The extract was washed with brine (100 mL), driedover anhydrous Na₂SO₄ and concentrated in vacuo. The residue wasrecrystalized in DCM to afford the compoundN-(3,5-dibromopyrazin-2-yl)-6-ethoxypicolinamide.

LC-MS: m/z 400.9, 402.9, 404.9 (M+H)⁺

Step D:N-(5-bromo-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide

A suspension of N-(3,5-dibromopyrazin-2-yl)-6-ethoxypicolinamide (1.0 g,2.5 mmol, 1 equiv), 2,6-dimethoxyaniline (380 mg, 2.5 mmol, 1 equiv),Pd(OAc)₂ (112 mg, 0.5 mmol, 0.2 equiv), Xantphos (576 mg, 1.0 mmol, 0.4equiv) and K₂CO₃ (680 mg, 3.0 mmol, 2 equiv) in 1,4-dioxane (10 mL) wasstirred at 120° C. via microwave irradiation for 2 hours under N₂atmosphere. The mixture was diluted with DCM (20 mL) and filteredthrough celite. The filtrate was concentrated in vacuo and the residuewas purified by flash chromatography (PE/EtOAc=4/1) to afford the titlecompoundN-(5-bromo-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide.

LC-MS: m/z 474.0, 476.0 (M+H)⁺

Step E:6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(Example 1)

A solution ofN-(5-bromo-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide(1.0 g, 2.1 mmol, 1 equiv) in AcOH (10 mL) was stirred at 120° C. viamicrowave irradiation for 2 hours. The mixture was cooled to roomtemperature. The precipitate was filtered off and washed with a mixtureof EtOAc/PE=1/2 (3*1 mL) to afford the title compound as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ: 8.75 (s, 1H), 8.04 (dd, J=7.4, 0.8 Hz, 1H),7.89 (dd, J=8.4, 7.4 Hz, 1H), 7.50 (t, J=8.4 Hz, 1H), 6.89 (d, J=8.4 Hz,3H), 3.60 (s, 6H), 3.40 (q, J=7.0 Hz, 2H), 1.05 (t, J=7.0 Hz, 3H).

LC-MS: m/z 456.1, 458.1 (M+H)⁺

Step F:N-(1-(2,6-dimethoxyphenyl-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide(Example 2)

A suspension of6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(150 mg, 0.33 mmol), methanesulfonamide (62 mg, 0.66 mmol, 2 equiv), CuI(125 mg, 0.66 mmol, 2 equiv), trans-N,N′-Dimethylcyclohexane-1,2-diamine(94 mg, 0.66 mmol, 2 equiv) and K₂CO₃ (137 mg, 0.99 mmol, 3 equiv) inDMF (5 mL) was stirred at 115° C. via microwave irradiation for 1.5 hourunder N₂ atmosphere. The reaction was washed with water (150 mL),followed by extraction with EtOAc (3*100 mL). The combined organic layerwas dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residuewas purified by flash chromatography (eluting with PE/EtOAc=20/1˜5/1) toobtain the title compound as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ: 11.05 (s, 1H), 8.27 (s, 1H), 7.95 (dd,J=7.4 Hz, J=0.8 Hz, 1H), 7.86 (t, J=7.8 Hz, 1H), 7.45 (t, J=8.4 Hz, 1H),6.81-6.87 (m, 3H), 3.57 (s, 6H), 3.39 (q, J=7.0 Hz, 2H), 3.20 (s, 3H),1.03 (t, J=7.0 Hz, 3H). LC-MS: m/z 471.0 (M+H)⁺

Example 3:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-phenylethanesulfonamide

The title compound was prepared according to general procedure A, stepF, starting from Example 1 by using benzylsulfonamide.

¹H NMR (400 MHz, DMSO-d₆) δ: 11.04 (s, 1H), 8.14 (s, 1H), 7.97 (dd,J=7.4 Hz, 0.8 Hz, 1H), 7.87 (t, J=7.8 Hz, 1H), 7.49 (t, J=8.4 Hz, 1H),7.31-7.33 (m, 3H), 7.12-7.14 (m, 2H), 6.83-6.90 (m, 3H), 4.68 (s, 2H),3.58 (s, 6H), 3.41 (q, J=7.0 Hz, 2H), 1.03 (t, J=7.0 Hz, 3H). LC-MS: m/z547.0 (M+H)⁺

Example 4:1-cyclopropyl-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

The title compound was prepared according to general procedure A, stepF, starting from Example 1 by using 1-cyclopropylmethanesulfonamide.

¹H NMR (400 MHz, DMSO-d₆) δ: 11.03 (s, 1H), 8.30 (s, 1H), 7.94 (dd,J=7.4 Hz, 0.8 Hz, 1H), 7.85 (t, J=7.8 Hz, 1H), 7.45 (t, J=8.4 Hz, 1H),6.81-6.87 (m, 3H), 3.57 (s, 6H), 3.39 (q, J=7.0 Hz, 2H), 3.27 (d, J=3.4Hz, 2H), 1.02 (t, J=7.0 Hz, 3H), 0.47 (d, J=4.0 Hz, 3H), 0.13 (d, J=2.2Hz, 2H). LC-MS: m/z 511.0 (M+H)⁺

Example 5:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)benzenesulfonamide

The title compound was prepared according to general procedure A, stepF, starting from Example 1 by using benzenesulfonamide.

¹H NMR (400 MHz, DMSO-d₆) δ: 11.53 (s, 1H), 8.24 (s, 1H), 7.93 (dd,J=7.4 Hz, 0.8 Hz, 1H), 7.83 (t, J=7.8 Hz, 1H), 7.66 (dd, J=8.4 Hz, 0.8Hz, 2H), 7.55 (t, J=8.4 Hz, 2H), 7.38 (t, J=7.8 Hz, 2H), 6.93 (d, J=4.4Hz, 2H), 6.81 (d, J=4 Hz 1H), 3.54 (s, 6H), 3.38 (q, J=7.0 Hz, 2H), 1.03(t, J=7.0 Hz, 3H). LC-MS: m/z 533.0 (M+H)⁺

Example 6:1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-6-(phenylethynyl)-1H-imidazo[4,5-b]pyrazine

And

Example 7:1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-6-phenethyl-1H-imidazo[4,5-b]pyrazine

Step A:1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-6-(phenylethynyl)-1H-imidazo[4,5-b]pyrazine(Example 6)

A suspension of6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(Example 1, 100 mg, 0.22 mmol, 1 equiv), ethynylbenzene (44.5 mg, 0.44mmol, 2 equiv), Pd(PPh₃)₂Cl₂ (15.3 mg, 0.022 mmol, 0.1 equiv), CuI (8.3mg, 0.044 mmol, 0.2 equiv) and Et₃N (66 mg, 0.66 mmol, 3.0 equiv) in DMF(5 mL) was bubbled with N₂ for 1 min followed by stirred at 80° C. for 4hours. The reaction mixture was diluted with water (50 mL) and extractedwith ethyl ether (3*100 mL). The combined organic phase was washed withbrine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated.The residue was purified by flash chromatography on silica gel(PE/EtOAc=1/1) to afford the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ: 8.85 (s, 1H), 8.07 (d, J=7.0 Hz, 1H),7.87-7.93 (m, 1H), 7.64-7.68 (m, 2H), 7.49-7.53 (m, 1H), 7.43-7.49 (m,3H), 6.90 (dd, J=8.4, 1.6 Hz, 3H), 3.61 (s, 6H), 3.41 (q, J=7.0 Hz, 2H),1.06 (t, J=7.0 Hz, 3H). LC-MS: m/z 478.2 (M+H)⁺

Step B:1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-6-phenethyl-1H-imidazo[4,5-b]pyrazine(Example 7)

A mixture of1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-6-(phenylethynyl)-1H-imidazo[4,5-b]pyrazine(70 mg, 0.157 mmol) and 10% Pd/C (7 mg) in EtOAc (10 mL) was stirredunder H₂ at room temperature overnight. The reaction mixture wasfiltered through celite and the filtrate was concentrated in vacuo. Theresidue was purified by flash chromatography on silica gel(PE/EtOAc=1/1) to afford the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ: 8.40 (s, 1H), 7.98 (d, J=7.4 Hz, 1H), 7.86(t, J=7.8 Hz, 1H), 7.47 (t, J=8.4 Hz, 1H), 7.19-7.26 (m, 2H), 7.09-7.18(m, 3H), 6.86 (dd, J=17.4, 8.4 Hz, 3H), 3.59 (s, 6H), 3.41 (q, J=7.0 Hz,2H), 3.13 (dd, J=8.4, 6.8 Hz, 2H), 2.96 (t, J=7.6 Hz, 2H), 1.05 (t,J=7.0 Hz, 3H).

LC-MS: m/z 482.2 (M+H)⁺

Example 8:N-Benzyl-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine-6-carboxamide

Step A: Methyl1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine-6-carboxylate

6-Bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(105 mg, 0.23 mmol, 1 equiv) was dissolved in MeOH. Then Pd(dppf)Cl₂ (33mg, 0.046 mmol, 0.2 equiv) and triethylamine (70 mg, 0.69 mmol, 3 equiv)were added. The suspension was degassed and purged with CO three times.Then the reaction mixture was stirred at 90° C. under 3 MPa overnight.The reaction mixture was filtered, concentrated and purified via columnchromatography (silica gel, eluting with 25% EtOAc in PE) to afford thetitle compound methyl1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine-6-carboxylate.

LC-MS: m/z 436.1 (M+H)⁺

Step B:N-Benzyl-1-(2,6-dimethoxyphenyl-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine-6-carboxamide(Example 8)

Methyl1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine-6-carboxylate(32.4 mg, 0.074 mmol, 1 equiv) and benzylamine (15 mg, 0.148 mmol, 2equiv) were charged into sealed tube and the mixture was heated at 90°C. for 2 h. Then the reaction mixture was purified via columnchromatography (silica gel, eluting with 25% EtOAc in PE) to afford thetitle compound.

¹H NMR (400 MHz, DMSO-d₆) δ: 9.21 (s, 1H), 8.85 (t, J=6.4 Hz, 1H), 8.04(d, J=6.8 Hz, 1H), 7.90 (t, J=7.2 Hz, 1H), 7.46 (t, J=8.4 Hz, 1H),7.23-7.30 (m, 5H), 6.88 (t, J=8.4 Hz, 3H), 4.50 (d, J=6.4 Hz, 2H), 3.59(s, 6H), 3.41 (q, J=7.0 Hz, 2H), 1.05 (t, J=7.0 Hz, 3H). LC-MS: m/z511.2 (M+H)⁺

Example 9:1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-N-methyl-1H-imidazo[4,5-b]pyrazin-6-amine

A mixture of6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(Example 1, 60 mg, 0.1 mmol, equiv), and CH₃NH₂ (aq., 40 wt %, 5 mL) wasstirred at 120° C. via microwave irradiation for 2 hours. The reactionmixture was concentrated and residue was purified by flashchromatography on silica gel (PE/EtOAc=1/2) to afford the titlecompound.

¹H NMR (400 MHz, DMSO-d₆) δ: 7.84 (s, 1H), 7.82 (dd, J=7.4, 1.0 Hz, 1H),7.73-7.79 (m, 1H), 7.40 (t, J=8.4 Hz, 1H), 7.19 (q, J=4.8 Hz, 1H), 6.83(d, J=8.4 Hz, 2H), 6.69 (dd, J=8.0, 1.0 Hz, 1H), 3.58 (s, 6H), 3.37 (q,J=7.0 Hz, 2H), 2.70 (d, J=4.8 Hz, 3H), 1.02 (t, J=7.0 Hz, 3H). LC-MS:m/z 407.2 (M+H)⁺

Step A: tert-butyl(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)carbamate

A suspension of6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(500 mg, 1.09 mmol, 1 equiv), BocNH₂ (255 mg, 2.18 mmol, 2 equiv),Pd(OAc)₂ (49 mg, 0.22 mmol, 0.2 equiv), Xantphos (252 mg, 0.44 mmol, 0.4equiv) and Cs₂CO₃ (711 mg, 2.18 mmol, 2 equiv) in 1.4-dioxane (10 mL)was stirred at 120° C. via microwave irradiation for 2 hours under N₂atmosphere. The mixture was filtered through celite and the filtrate wasconcentrated in vacuo. The residue was purified by flash chromatography(PE/EtOAc=2/1) to afford the title compound tert-butyl(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)carbamate.

LC-MS: m/z 493.2 (M+H)⁺

Step B:1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-amine(Example 10)

A mixture of tert-butyl(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)carbamate(350 mg, 0.71 mmol, 1 equiv) and HCl in dioxane (4 mol/L, 20 mL) at 0°C. The mixture was then stirred at room temperature for 4 hours. Thereaction mixture was concentrated and residue was purified by flashchromatography on silica gel (100% EtOAc) to afford Example 10.

¹H NMR (400 MHz, DMSO-d₆) δ: 7.83-7.89 (m, 2H), 7.79 (t, J=7.8 Hz, 1H),7.41 (t, J=8.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 2H), 6.72 (d, J=8.0 Hz, 1H),6.64 (s, 2H), 3.60 (s, 6H), 3.42 (q, J=7.0 Hz, 2H), 1.04 (t, J=7.0 Hz,3H).

LC-MS: m/z 393.2 (M+H)⁺

Example 11:N,N-dibenzyl-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-amine

A mixture of compound Example 10 (50 mg, 0.13 mmol, 1 equiv) and NaH(10.2 mg, 0.26 mmol, 2 equiv) in DMF (5 mL) was stirred at 0° C. for 30minutes. Bromomethylbenzene (24 mg, 0.14 mmol, 1.1 equiv) was added andthe mixture was stirred at room temperature overnight. The reactionmixture was diluted with water (30 mL) and extracted with ethyl ether(3*50 mL). The combined organic phase was washed with brine (30 mL),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by flash chromatography on silica gel(PE/EtOAc=1/1) to afford the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ: 7.90 (s, 1H), 7.85 (dd, J=7.4, 0.8 Hz, 1H),7.78 (t, J=7.8 Hz, 1H), 7.43 (t, J=8.4 Hz, 1H), 7.18-7.32 (m, 10H), 6.85(d, J=8.4 Hz, 2H), 6.73 (dd, J=8.0, 0.8 Hz, 1H), 4.77 (s, 4H), 3.55 (s,6H), 3.37 (q, J=7.0 Hz, 2H), 1.01 (t, J=7.0 Hz, 3H). LC-MS: m/z 573.2(M+H)⁺

Example 12:1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-N,N-dimethyl-1H-imidazo[4,5-b]pyrazin-6-amine

A mixture of compound Example 10 (50 mg, 0.13 mmol, 1 equiv), and NaH(15.3 mg, 0.38 mmol, 3 equiv) in DMF (5 mL) was stirred at 0° C. for 30min. iodomethane (54.3 mg, 0.38 mmol, 3 equiv) was added and the mixturewas stirred at room temperature overnight. The reaction mixture wasdiluted with water (30 mL) and extracted with ethyl ether (3*50 mL). Thecombined organic phase was washed with brine (30 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by flash chromatography on silica gel (PE/EtOAc=3/7) to affordthe desired product.

¹H NMR (400 MHz, DMSO-d₆) δ: 8.08 (s, 1H), 7.84 (dd, J=7.4, 1.0 Hz, 1H),7.75-7.82 (m, 1H), 7.40 (t, J=8.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 2H), 6.71(dd, J=8.0, 1.0 Hz, 1H), 3.57 (s, 6H), 3.40-3.34 (m, 2H), 3.02 (s, 6H),1.02 (t, J=7.0 Hz, 3H). LC-MS: m/z 421.2 (M+H)⁺

Example 13:N-benzyl-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-amine

To a well-stirred red suspension of1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-amine(Example 10, 60 mg, 0.15 mmol, 1 equiv) in 1, 2-dichloroethane (20 mL),benzylaldehyde (65 mg, 0.61 mmol, 4 equiv) was added, and the reactionflask was immersed in an ice bath. Then AcOH (37 mg, 0.61 mmol, 4 equiv)was added followed by the addition of sodium triacetoxyborohydride (130mg, 0.61 mmol, 4 equiv) in small portions over a 15 min period. Theresulting suspension was slowly allowed to warm to 50° C. and stirredovernight. The reaction was quenched by a slow addition of saturatedNaHCO₃ (20 mL) while stirring at 0° C. The biphasic mixture was stirredfor 30 min and extracted with DCM (3*25 mL). The combined organic phasewas washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel (PE/EtOAc=1/1) to afford the desired product.

¹H NMR (400 MHz, DMSO-d₆) δ: 7.88 (s, 1H), 7.74-7.84 (m, 3H), 7.42 (t,J=8.4 Hz, 1H), 7.28-7.17 (m, 5H), 6.83 (d, J=8.4 Hz, 2H), 6.70 (dd,J=8.0, 1.0 Hz, 1H), 4.30 (d, J=6.0 Hz, 2H), 3.54 (s, 6H), 3.34-3.40 (m,2H), 1.01 (t, J=7.0 Hz, 3H). LC-MS: m/z 483.2 (M+H)⁺

Example 14:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-2-phenylacetamide

A mixture of1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-amine(Example 10, 50 mg, 0.13 mmol, 1 equiv), and NaH (15.3 mg, 0.38 mmol, 3equiv) in DMF (5 mL) was stirred at 0° C. for 30 min. 2-Phenylacetylchloride (21 mg, 0.13 mmol, 1 equiv) was added and the mixture wasstirred at room temperature overnight. The reaction mixture was dilutedwith water (30 mL) and extracted with ethyl ether (3*50 mL). Thecombined organic phase was washed with brine (30 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by flash chromatography on silica gel (PE/EtOAc=3/7) to affordthe desired product.

¹H NMR (400 MHz, DMSO-d₆) δ: 11.11 (s, 1H), 9.33 (s, 1H), 7.99 (d, J=7.4Hz, 1H), 7.85 (t, J=7.8 Hz, 1H), 7.46 (t, J=8.4 Hz, 1H), 7.18-7.37 (m,6H), 6.86 (d, J=8.4 Hz, 2H), 3.74 (s, 2H), 3.60 (s, 6H), 3.39 (q, J=7.0Hz, 2H), 1.05 (t, J=7.0 Hz, 3H). LC-MS: m/z 511.2 (M+H)⁺

Example 15:5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine

And

Example 16:1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-amine

Step A: N-(3-bromo-6-chloropyrazin-2-yl)-6-ethoxypicolinamide

The mixture of ethyl 6-ethoxypicolinate (500 mg, 2.56 mmol, 1 equiv) and3-bromo-6-chloropyrazin-2-amine (530 mg, 2.56 mmol, 1 equiv) in toluenewas cooled to 0° C. and AlMe₃ was added dropwise. Then the mixture wasstirred at 100° C. for 16 hours. The mixture was quenched with NH₄Clsolution and extracted with EtOAc (3*20 mL). The combined organic layerwas dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residuewas purified by flash chromatography on silica gel (PE/EtOAc=10/1) toafford the title compoundN-(3-bromo-6-chloropyrazin-2-yl)-6-ethoxypicolinamide.

¹H NMR (400 MHz, DMSO-d₆) δ: 10.94 (s, 1H), 8.50 (s, 1H), 7.99 (d, J=7.6Hz, 1H), 7.68-7.82 (m, 1H), 7.07-7.27 (m, 1H), 4.52 (d, J=7.0 Hz, 2H),1.40 (t, J=7.0 Hz, 3H). LC-MS: m/z 357.7 (M+H)⁺

Step B:N-(6-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide

The mixture of N-(3-bromo-6-chloropyrazin-2-yl)-6-ethoxypicolinamide(500 mg, 1.4 mmol, 1 equiv), 2,6-dimethoxyaniline (430 mg, 2.8 mmol, 2equiv), Xantphos (162 mg, 0.28 mmol, 2 equiv), Pd₂(dba)₃ (128 mg, 0.14mmol, 0.1 equiv), potassium 2-methylpropan-2-olate (297 mg, 2.8 mmol, 2equiv) in toluene (10 mL) was stirred at 110° C. for 16 hours under N₂atmosphere. The mixture was filtered and concentrated in vacuo. Theresidue was purified by flash column chromatography on silica gel(PE/EtOAc=10/1) to afford the title compoundN-(6-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide.

¹H NMR (400 MHz, CDCl₃) δ: 10.11 (s, 1H), 8.40 (s, 1H), 8.02 (s, 1H),7.92 (d, J=7.2 Hz, 1H), 7.77 (t, J=8.8 Hz, 1H), 7.13 (t, J=8.4 Hz, 1H),6.97 (d, J=8.0 Hz, 1H), 6.65 (d, J=8.4 Hz, 2H), 4.48 (q, J=7.2 Hz, 2H),3.82 (s, 6H), 1.46-1.52 (m, 3H). LC-MS: m/z 429.7 (M+H)⁺

Step C:5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(Example 15)

N-(6-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide(280 mg, 0.56 mmol, 1 equiv) in AcOH (20 mL) was stirred at 120° C. for1 hour under MW. The mixture was concentrated in vacuo. The residue waswashed with ether, filtered and dried to afford the desired product.

¹H NMR (400 MHz, CDCl₃) δ: 8.27 (s, 1H), 8.13-8.20 (m, 1H), 7.69 (t,J=8.4 Hz, 1H), 7.39 (t, J=8.4 Hz, 1H), 6.65-6.77 (m, 3H), 3.62 (s, 6H),3.43 (q, J=7.2 Hz, 2H), 1.09 (t, J=7.2 Hz, 3H). LC-MS: m/z 411.7 (M+H)⁺

Step D: tert-butyl(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)carbamate

The mixture of5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(80 mg, 0.19 mmol, 1 equiv), tert-butyl carbamate (46 mg, 0.38 mmol, 2equiv), Xantphos (22 mg, 0.038 mmol, 0.2 equiv), Pd₂(dba)₃ (17 mg, 0.019mmol, 0.1 equiv), potassium 2-methylpropan-2-olate (43 mg, 0.38 mmol, 2equiv) in toluene (5 mL) was stirred at 110° C. for 16 hours under N₂atmosphere. The mixture was filtered and concentrated in vacuo. Theresidue was purified by flash chromatography on silica gel(PE/EtOAc=3/1) to afford the title compound tert-butyl(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)carbamate.

¹H NMR (400 MHz, CD₃OD) δ: 8.91 (s, 1H), 7.89-7.87 (d, J=7.2 Hz, 1H),7.79-7.77 (t, J=7.2 Hz, 1H), 7.46-7.44 (t, J=8.4 Hz, 1H), 6.84-6.75 (m,3H), 3.64 (s, 6H), 3.51-3.46 (m, 2H), 1.55 (s, 9H), 1.11-1.09 (t, J=7.2Hz, 3H). LC-MS: m/z 492.7 (M+H)⁺

Step E:1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-amine(Example 16)

tert-butyl(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)carbamate (30 mg, 0.06 mmol, 1 equiv) in HCl/MeOH (4 mol/L, 10 mL) wasstirred at room temperature for 6 hours. The mixture was concentrated invacuo and residue was washed with ether to afford the desired product.

¹H NMR (400 MHz, CD₃OD) δ: 7.96 (s, 1H), 7.80 (t, J=8.0 Hz, 1H),7.52-7.63 (m, 2H), 6.85-6.97 (m, 3H), 3.80 (q, J=7.2 Hz, 2H), 3.70 (s,6H), 1.19 (t, J=7.2 Hz, 3H). LC-MS: m/z 393.3 (M+H)⁺

Example 17:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)-2-phenylacetamide

The mixture of5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(Example 15, 60 mg, 0.15 mmol, 1 equiv), 2-phenylacetamide (19.7 mg,0.15 mmol, 1 equiv), Xantphos (17 mg, 0.03 mmol, 0.2 equiv), Pd₂(dba)₃(13 mg, 0.015 mmol, 0.1 equiv), Cs₂CO₃ (95 mg, 0.3 mmol, 2 equiv) indioxane (5 mL) was stirred at 110° C. for 16 hours under N₂ atmosphere.The mixture was filtered and concentrated in vacuo. The residue waspurified by flash chromatography on silica gel (PE/EtOAc=3/1) to affordthe title compound.

¹H NMR (400 MHz, CDCl₃) δ: 9.34 (s, 1H), 8.12 (d, J=7.2 Hz, 2H), 7.66(t, J=7.2 Hz, 1H), 7.33-7.41 (m, 5H), 6.63-6.73 (m, 3H), 3.85 (s, 2H),3.55-3.66 (m, 6H), 3.43 (q, J=7.2 Hz, 2H), 1.08 (t, J=7.2 Hz, 3H).LC-MS: m/z 511.3 (M+H)⁺

Example 18:1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine

Step A: ethyl 6-ethoxypicolinate

To a solution of 6-hydroxypicolinic acid (12 g, 86.33 mmol) in DCM (250ml) was added Ag₂CO₃ (48 g, 174 mmol), followed by adding EtI (27.6 ml,345.32 mmol) dropwise. The mixture was stirred at 25° C. for 12 hr. andfiltered. The filtrate was concentrated in vacuum to give ethyl6-ethoxypicolinate as a gray oil, which was used in the next stepwithout further purification.

LC-MS: m/z 196.3 (M+H)⁺

Step B: (6-ethoxypyridin-2-yl)methanol

To a solution of ethyl 6-ethoxypicolinate (5.8 g, 29.7 mmol) in THF (60ml) was added LiAlH₄ (15 ml, 1M THF sol.) dropwise at 0° C. The reactionmixture was stirred at 25° C. for 3 hr and quenched with H₂O/EA. Thecollected organic layers were dried over Na₂SO₄ and concentrated invacuum. The residue was purified by silica gel chromatograph to give(6-ethoxypyridin-2-yl)methanol.

LC-MS: m/z 154.3 (M+H)⁺

Step C: 6-ethoxypicolinaldehyde

To a solution of (6-ethoxypyridin-2-yl)methanol (3 g, 19.61 mmol) in1,4-dioxane (30 ml) was added MnO₂ (12 g, 137.25 mmol) and the reactionmixture was refluxed for 3 hr. The reaction mixture was filtered and thefiltrate was concentrated in vacuum to give 6-ethoxypicolinaldehyde.

LC-MS: m/z 152.3 (M+H)⁺

Step D: 3-chloro-N-(2,6-dimethoxyphenyl)pyrazin-2-amine

To a solution of 2,3-dichloropyrazine (0.918 g, 6 mmol) in THF (15 mL)was added KHMDS (1 N in TMF, 6 mL, 6 mmol) slowly at 0° C. and themixture was stirred at 0° C. for 15 min, followed by adding a solutionof 3-5 (0.74 g, 5 mmol) in THF (5 mL) dropwise at 0° C. The dark-greenmixture was stirred at room temperature for 3 h, poured into ice-water(40 mL) and extracted with EA (10 mL*3). The combined organic layer wasdried over Na₂SO₄ and concentrated in vacuum to get the residue, whichwas purified by column chromatography (PE:EA=97:3˜66:34) to give3-chloro-N-(2,6-dimethoxyphenyl)pyrazin-2-amine.

Step E: N-(2,6-dimethoxyphenyl)tetrazolo[1,5-a]pyrazin-8-amine

A mixture of 3-chloro-N-(2,6-dimethoxyphenyl)pyrazin-2-amine (0.14 g,0.53 mmol) and NaN₃ (86 mg, 1.32 mmol) in DMSO (3 mL) was stirred at130° C. for 18 hr. The solution was poured into 10 mL of ice-water andextracted with EA. The organic layer was dried and evaporated to afforddark-red oil which was used to the next step without any purification.

LC-MS: m/z 273.1 (M+H)⁺

Step F: N-(2,6-dimethoxyphenyl)tetrazolo[1,5-a]pyrazin-8-amine

To a solution of crudeN-(2,6-dimethoxyphenyl)tetrazolo[1,5-a]pyrazin-8-amine (143.7 mg, 0.53mmol) in con.HCl aq. (3 mL) was added SnCl₂.H₂O (1.19 g, 5.3 mmol) andthe mixture was stirred at 115° C. for 2 h. After cooled to roomtemperature, the mixture was added K₂CO₃ to adjust pH=8-9 and filtered.The filtrate was extracted by EA and the organic layer was dried overNa₂SO₄ and concentrated in vacuum to get the residue, which was purifiedby column chromatography (PE:EA=97:3˜66:34) to affordN-(2,6-dimethoxyphenyl)tetrazolo[1,5-a]pyrazin-8-amine.

LC-MS: m/z 247.1 (M+H)⁺

Step G:1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine

A mixture of N-(2,6-dimethoxyphenyl)tetrazolo[1,5-a]pyrazin-8-amine (70mg, 0.285 mmol) and 6-ethoxypicolinaldehyde (43 mg, 0.285 mmol) in AcOH(1 mL) and stirred at 110° C. for 10 min under MW. The mixture wasconcentrated and the residue was purified by prep-HPLC to give1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine.

LC-MS: m/z 378.2 (M+H)⁺

Example 19:N-(5-(2,6-dimethoxyphenyl)-6-(6-ethoxypyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)methanesulfonamide

Step A: 2-bromo-6-ethoxypyridine

To a solution of 2,6-dibromopyridine (20 g, 84 mmol, 1 equiv) in EtOH(200 mL) was added sodium ethanolate (22.9 g, 336 mmol, 4 equiv). Themixture was stirred at reflux temperature for 3 days. The reactionmixture was concentrated in vacuo. To the residue was added water (300mL) and the mixture was extracted with DCM (2*300 mL). The combinedorganic layers was dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by silica gel chromatography (100% PE)to afford the title compound.

LC-MS: m/z 202.0, 204.0 (M+H)⁺

Step B: 2-ethoxy-6-((trimethylsilyl)ethynyl)pyridine

A suspension of 2-bromo-6-ethoxypyridine (13.0 g, 64 mmol, 1 equiv),ethynyltrimethylsilane (10.11 g, 103 mmol, 1.6 equiv), Pd(PPh₃)₂Cl₂(1.13 g, 1.6 mmol, 0.025 equiv) and CuI (610 mg, 3.2 mmol, 0.05 equiv)in Et₃N (230 mL) was stirred at 85° C. for 2.5 hours under N₂atmosphere. The mixture was filtered through celite. The filtrate wasconcentrated in vacuo and the residue was purified by flashchromatography (100% PE) to afford the title compound6-chloro-3-((6-ethoxypyridin-2-yl)ethynyl)pyrazin-2-amine.

LC-MS: m/z 220.3 (M+H)⁺

Step C: 2-ethoxy-6-ethynylpyridine

To a solution of 2-ethoxy-6-((trimethylsilyl)ethynyl)pyridine (11 g,50.2 mmol, 1 equiv) in THF (100 mL) was added TBAF (50 mL, 50.2 mmol, 1equiv). The resulted mixture was stirred at room temperature for 16hours. The reaction solution was concentrated in vacuo and the residuewas purified by flash chromatography (PE/EtOAc=100/1) to afford thetitle compound 2-ethoxy-6-ethynylpyridine.

LC-MS: m/z 148.1 (M+H)⁺

Step D: 6-chloro-3-((6-ethoxypyridin-2-yl)ethynyl)pyrazin-2-amine

A suspension of 2-ethoxy-6-ethynylpyridine (2.0 g, 13.6 mmol, 1 equiv),3-bromo-6-chloropyrazin-2-amine (2.8 g, 13.6 mmol, 1 equiv),Pd(PPh₃)₂Cl₂ (238 mg, 0.34 mmol, 0.03 equiv) and CuI (129 mg, 0.68 mmol,0.06 equiv) in Et₃N (80 mL) was stirred at 85° C. for 2 hours under N₂atmosphere. The mixture was diluted with EtOAc (120 mL) and filteredthrough celite. The filtrate was concentrated in vacuo and the residuewas purified by flash chromatography (PE/EtOAc=6/1) to afford the titlecompound 6-chloro-3-((6-ethoxypyridin-2-yl)ethynyl)pyrazin-2-amine.

LC-MS: m/z 275.1 (M+H)⁺

Step E: 3-chloro-6-(6-ethoxypyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazine

To a solution of6-chloro-3-((6-ethoxypyridin-2-yl)ethynyl)pyrazin-2-amine (2.3 g, 8.4mmol, 1 equiv) in THF (50 mL) was added NaH (0.5 g, 12.6 mmol, 1.5equiv) at 0° C. The mixture was stirred at room temperature for 1 hourthen heated to 60° C. for overnight. The mixture was quenched with 0.5mL H₂O, then concentrated under vacuo to dry to give a residue, whichwas purified by flash chromatography (PE/EtOAc=5/1) to afford the titlecompound 3-chloro-6-(6-ethoxypyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazine.

LC-MS: m/z 275.1 (M+H)⁺

Step F:3-chloro-5-(2,6-dimethoxyphenyl)-6-(6-ethoxypyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazine

A suspension of3-chloro-6-(6-ethoxypyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazine (1 g, 3.65mmol, 1.0 equiv), (2,6-dimethoxyphenyl)boronic acid (1.3 g, 7.3 mmol, 2equiv), Cu(OAc)₂ (1.3 g, 7.3 mmol, 2 equiv), dry pyridine (865 mg, 11mmol, 3 equiv) and 4 Å molecular sieve in dry DCE (10 mL) was stirred at25° C. for 30 hours under 02 atmosphere. The reaction was diluted withDCM (50 mL) and filtered through celite. The filtrate was concentratedin vacuo and the residue was purified by flash chromatography(PE/EtOAc=5/1) to afford the title compound3-chloro-5-(2,6-dimethoxyphenyl)-6-(6-ethoxypyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazine.

LC-MS: m/z 411.1 (M+H)⁺

Step G:N-(5-(2,6-dimethoxyphenyl)-6-(6-ethoxypyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)methanesulfonamide

A suspension of3-chloro-5-(2,6-dimethoxyphenyl)-6-(6-ethoxypyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazine(30 mg, 0.07 mmol, 1.0 equiv), methanesulfonamide (28 mg, 0.28 mmol, 4equiv), trans-N,N′-Dimethylcyclohexane-1,2-diamine (22 mg, 0.14 mmol, 2equiv), CuI (29 mg, 0.14 mmol, 2 equiv) and K₂CO₃ (30 mg, 0.22 mmol, 3equiv) in DMF (2 mL) was stirred at 115° C. via microwave irradiationfor 2 hours under N₂ atmosphere. The reaction mixture was poured intoH₂O (20 mL) and extracted with EtOAc (3*20 mL). The extracts were washedwith water (10 mL) and brine (10 mL), dried over MgSO₄ and concentratedin vacuo. The residue was purified by flash chromatography(PE/EtOAc=1/1) to afford the title compoundN-(5-(2,6-dimethoxyphenyl)-6-(6-ethoxypyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)methanesulfonamide.

¹H NMR (DMSO-d₆) δ: 8.17 (s, 1H), 7.69 (t, J=7.6 Hz, 1H), 7.36-7.40 (m,2H), 7.31 (s, 1H), 6.78 (d, J=8.4 Hz, 2H), 6.61 (d, J=8.0 Hz, 1H),3.53-3.55 (m, 2H), 3.52 (s, 6H), 3.12 (s, 3H), 1.08 (t, J=7.2 Hz, 3H).

LC-MS: m/z 470.0 (M+H)⁺

Example 20:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyridin-6-yl)methanesulfonamide

Step A: N-(5-bromo-3-iodopyridin-2-yl)-6-ethoxypicolinamide

To a solution of 5-bromo-3-iodopyridin-2-amine compound (2 g, 6.7 mmol,1.1 equiv) in toluene (50 mL) was added Al(Me)₃ (1.6 mol/L in toluene,7.6 mL, 12.2 mmol, 2 equiv) drop wise at room temperature. After themixture was stirred at 50° C. for 30 min, ethyl 6-ethoxypicolinate (1.19g, 6.1 mmol, 1 equiv) was added and the mixture was stirred at 110° C.for 2 hours. The reaction mixture was quenched with water (50 mL),followed by extraction with EtOAc (3*50 mL). The combined organic layerswas washed with brine (50 mL), dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash chromatographyeluting with PE/EtOAc (20/1-5/1) to afford the title compoundN-(5-bromo-3-iodopyridin-2-yl)-6-ethoxypicolinamide.

LC-MS: m/z 447.9, 449.9 (M+H)⁺

Step B:N-(5-bromo-3-((2,6-dimethoxyphenyl)amino)pyridin-2-yl)-6-ethoxypicolinamide

A suspension of N-(5-bromo-3-iodopyridin-2-yl)-6-ethoxypicolinamide (200mg, 0.45 mmol, 1 equiv), 2,6-dimethoxyaniline (68 mg, 0.45 mmol, 1equiv), Pd₂(dba)₃ (82 mg, 0.09 mmol, 0.1 equiv), Xantphos (208 mg, 0.36mmol, 0.8 equiv) and Cs₂CO₃ (292 mg, 0.87 mmol, 2 equiv) in 1,4-dioxane(50 mL) was stirred at 120° C. via microwave irradiation for 2 hoursunder N₂ atmosphere. The mixture was diluted with water (30 mL),followed by extraction with EtOAc (3*20 mL). The combined organic layerswas dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residuewas purified by prep-TLC (PE/EtOAc=5/1) to afford the title compoundN-(5-bromo-3-((2,6-dimethoxyphenyl)amino)pyridin-2-yl)-6-ethoxypicolinamide.

LC-MS: m/z 473.0, 475.0 (M+H)⁺

Step C:6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyridine

To a solution ofN-(5-bromo-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide(100 mg, 0.21 mmol, 1 equiv) in AcOH (10 mL) was added 1 drop of POCl₃.The mixture was stirred at 120° C. via microwave irradiation for 2hours. The mixture was cooled to room temperature, evaporated and theresidue was purified by prep TLC (PE/EtOAc=1/1) to afford the titlecompound6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyridine.

LC-MS: m/z 455.0, 457.0 (M+H)⁺

Step D:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyridin-6-yl)methanesulfonamide

A suspension of6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(40 mg, 0.09 mmol, 1 equiv), methanesulfonamide (17 mg, 0.18 mmol, 2equiv), CuI (34 mg, 0.18 mmol, 2 equiv),trans-N,N′-Dimethylcyclohexane-1,2-diamine (25 mg, 0.18 mmol, 2 equiv)and K₂CO₃ (37 mg, 0.27 mmol, 3 equiv) in DMF (5 mL) was stirred at 115°C. via microwave irradiation for 1.5 hour under N₂ atmosphere. Thereaction was diluted with water (15 mL) and extracted with EtOAc (3*50mL). The combined organic layers was dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by prep TLC(PE/EtOAc=1/2) to obtain the title compoundN-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyridin-6-yl)methanesulfonamide.

¹H NMR (DMSO-d₆) δ: 9.88 (br. s., 1H), 8.38 (d, J=2.4 Hz, 1H), 7.91 (dd,J=7.4 Hz, 0.8 Hz, 1H), 7.84 (t, J=7.8 Hz, 1H), 7.47 (t, J=8.4 Hz, 1H),7.19 (d, J=2.4 Hz, 1H), 6.89 (d, J=8.5 Hz, 2H), 6.79 (dd, J=8.1, 0.9 Hz,1H), 3.58 (s, 6H), 3.39 (q, J=7.2 Hz, 2H), 2.96 (s, 3H), 1.02 (t, J=7.2Hz, 3H).

LC-MS: m/z 470.1 (M+H)⁺

Example 21:N-(5-(2,6-dimethoxyphenyl)-6-(6-ethoxypyridin-2-yl)-5H-imidazo[4,5-c]pyridazin-3-yl)methanesulfonamide

Step A: 6-chloropyridazin-3-amine

A suspension of 3,6-dichloropyridazine (10 g, 67 mmol, 1 equiv) in 25%aqueous ammonia (50 mL) was heated at 120° C. for about 12 h in aPTFE-lined pressure reactor. Upon cooling to room temperature, theresulting crystalline solids were collected by filtration, washed withwater and dried to afford the title compound 6-chloropyridazin-3-amine.

LC-MS: m/z 130.0 (M+H)⁺

Step B: 4-bromo-6-chloropyridazin-3-amine

To a solution of 6-chloropyridazin-3-amine (6.2 g, 48 mmol, 1 equiv) inmethanol (200 mL) was added NaHCO₃ (8.1 g, 96 mmol, 2 equiv). After themixture was stirred at room temperature for 30 min, bromine (11.5 g, 72mmol, 1.5 equiv) was added drop wise. Then reaction mixture was stirredfor another 16 h and concentrated under vacuum to obtain a residue. Theresidue was purified by silica gel column chromatography (eluting with40 percent EtOAc in hexane) to afford the title compound4-bromo-6-chloropyridazin-3-amine.

LC-MS: m/z 207.9, 209.9 (M+H)⁺

Step C: N-(4-bromo-6-chloropyridazin-3-yl)-6-ethoxypicolinamide

To a solution of 6-ethoxypicolinic acid (2.3 g, 13.9 mmol, 1.2 equiv)and Oxalyl chloride (2.2 g, 17.4 mmol, 1.5 equiv) in DCM (50 mL) wasadded DMF (0.1 mL) at 0° C. The resulted mixture was stirred at roomtemperature for 1 h. The reaction solution was concentrated in vacuo toafford 6-ethoxypicolinoyl chloride which was used directly. To asolution of 4-bromo-6-chloropyridazin-3-amine (2.4 g, 11.6 mmol, 1equiv) in DMF (50 mL) was added NaH (1.4 g, 34.8 mmol, 3 equiv) at RT.The mixture was stirred at room temperature for 1 h, then a solution of6-ethoxypicolinoyl chloride in DMF (50 mL) was added. The mixture wasstirred at room temperature for overnight. The reaction mixture wasquenched with ammonium chloride solution (aq., 100 mL) and extractedwith DCM (3*150 mL). The combined organic layers was washed with brine(100 mL), dried over anhydrous Na₂SO₄, and concentrated in vacuo. Theresidue was recrystalized in DCM to afford the title compoundN-(4-bromo-6-chloropyridazin-3-yl)-6-ethoxypicolinamide.

LC-MS: m/z 356.9, 358.9 (M+H)⁺

Step D:N-(6-chloro-4-((2,6-dimethoxyphenyl)amino)pyridazin-3-yl)-6-ethoxypicolinamide

A suspension of N-(4-bromo-6-chloropyridazin-3-yl)-6-ethoxypicolinamide(500 mg, 1.4 mmol, 1 equiv), 2,6-dimethoxyaniline (214 mg, 1.4 mmol, 1equiv), Pd(OAc)₂ (63 mg, 0.28 mmol, 0.2 equiv), Xantphos (324 mg, 0.56mmol, 0.4 equiv) and K₂CO₃ (386 mg, 2.8 mmol, 2.0 equiv) in 1,4-dioxane(10 mL) was stirred at 120° C. via microwave irradiation for 2 hoursunder N₂ atmosphere. The mixture was filtered through celite and thefiltrate was concentrated in vacuo. The residue was purified by flashchromatography (DCM/MeOH=100/1) to afford the desired productN-(6-chloro-4-((2,6-dimethoxyphenyl)amino)pyridazin-3-yl)-6-ethoxypicolinamide.

LC-MS: m/z 430.1 (M+H)⁺

Step E:chloro-7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazine

A solution ofN-(6-chloro-4-((2,6-dimethoxyphenyl)amino)pyridazin-3-yl)-6-ethoxypicolinamide(110 mg, 0.25 mmol) in AcOH (10 mL) was stirred at 120° C. via microwaveirradiation for 2 hours. After the reaction solution was cooled to roomtemperature, the light yellow precipitate was filtered off and rinsedwith EtOAc/PE=1/2 (2*0.5 mL) to afford the title compoundchloro-7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazine.

¹H NMR (400 MHz, DMSO-d&) S 8.05 (dd, J=7.4, 0.8 Hz, 1H), 7.93 (dd,J=8.4, 7.4 Hz, 1H), 7.67 (s, 1H), 7.50 (t, J=8.4 Hz, 1H), 6.93 (dd,J=8.4, 0.8 Hz, 1H), 6.89 (d, J=8.4 Hz, 2H), 3.60 (s, 6H), 3.40 (q, J=7.2Hz, 2H), 1.04 (t, J=7.2 Hz, 3H).

LC-MS: m/z 412.1 (M+H)⁺

Step E:N-(7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazinyl)methanesulfonamide

A suspension ofchloro-7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazine(48 mg, 0.12 mmol, 1 equiv), methanesulfonamide (22 mg, 0.23 mmol, 2equiv), CuI (44 mg, 0.23 mmol, 2 equiv),trans-N,N′-Dimethylcyclohexane-1,2-diamine (33 mg, 0.23 mmol, 2 equiv)and K₂CO₃ (48 mg, 0.23 mmol, 3 equiv) in DMF (2 mL) was stirred at 130°C. via microwave irradiation for 1.5 hour under N₂ atmosphere. Thereaction solution was diluted with water (150 mL) and extracted withEtOAc (3*100 mL). The combined organic layers was dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by flashchromatography (eluting with DCM/MeOH=100/1) to afford the titlecompound as yellow solid (30 mg, 55% yield).

¹H NMR (400 MHz, DMSO-d₆) δ 10.78 (s, 1H), 8.01 (dd, J=7.4, 0.8 Hz, 1H),7.91 (dd, J=8.4, 7.4 Hz, 1H), 7.50 (t, J=8.4 Hz, 1H), 6.91 (dd, J=8.4,1.2 Hz, 4H), 3.61 (s, 6H), 3.39 (q, J=7.2 Hz, 2H), 3.22 (s, 3H), 1.03(t, J=7.2 Hz, 3H).

LC-MS: m/z 471.1 (M+H)⁺

Step A: N-(3-bromo-5-chloropyrazin-2-yl)-6-ethoxypicolinamide

To a mixture of 3-bromo-5-chloropyrazin-2-amine (14.1 g, 67.6 mmol, 1.0equiv) and toluene (60 mL) was added AlMe₃ (2 mol/L, 51 mL, 102 mmol,1.5 equiv) and the resulted mixture was stirred at 55° C. for 30 mins.Ethyl 6-ethoxypicolinate (14.5 g, 74.4 mmol, 1.1 equiv) was added, andthe mixture was stirred at 110° C. for 1.5 h. The mixture was quenchedwith 1N HCl (102 mL, 102 mmol, 1.5 equiv) and extracted with DCM (3*500mL). The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was re-slurried in DCM to afford the title compoundN-(3-bromo-5-chloropyrazin-2-yl)-6-ethoxypicolinamide as a light yellowsolid (12 g, 50% yield).

LC-MS: m/z 356.9, 358.9 (M+H)⁺

Step B:N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide

A suspension of N-(3-bromo-5-chloropyrazin-2-yl)-6-ethoxypicolinamide (1g, 2.8 mmol, 1.0 equiv), 2,6-dimethoxyaniline (475 mg, 3.4 mmol, 1.1equiv), Pd(OAc)₂ (126 mg, 0.56 mmol, 0.2 equiv), Xantphos (650 mg, 1.12mmol, 0.4 equiv) and K₂CO₃ (772 mg, 5.6 mmol, 2.0 equiv) in 1,4-dioxane(15 mL) was stirred at 120° C. via microwave irradiation under N₂atmosphere for 2 h. The mixture was filtered through celite and thefiltrate was concentrated in vacuo. The residue was purified by flashcolumn chromatography (100% DCM) to afford the desired productN-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamideas a yellow solid (6.3 g, 52% yield).

LC-MS: m/z 430.1 (M+H)⁺

Step C:6-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine

A solution ofN-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide(2.0 g, 4.66 mmol) in AcOH (10 mL) was stirred at 130° C. via microwaveirradiation for 2 hours. The mixture was cooled to room temperature, theprecipitate was filtered off and washed with EtOAc/PE=1/2 to afford thetitle compound6-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineas a light yellow solid (1.6 g, 83% yield).

LC-MS: m/z 412.1 (M+H)⁺

Step D:N-(1-(2,6-dimethoxyphenyl-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide(Example 2)

A suspension of6-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(1 g, 2.43 mmol), methanesulfonamide (462 mg, 4.87 mmol, 3.0 equiv), CuI(924 mg, 4.87 mmol, 3.0 equiv),trans-N,N′-Dimethylcyclohexane-1,2-diamine (691 mg, 4.87 mmol, 3.0equiv) and K₂CO₃ (1006 mg, 7.29 mmol, 3 equiv) in DMF (10 mL) wasstirred at 130° C. via microwave irradiation for 1.5 hour under N₂atmosphere. The mixture was diluted with EtOAc (30 mL) and filteredthrough celite. The filtrate was poured onto aqueous K₂CO₃ (2 mol/L, 50mL), stirred for 15 mins. Then the aqueous phase was separated andwashed by EtOAc (2*30 mL). The aqueous phase was adjusted to pH=4 withformic acid and extracted with DCM (3*100 mL). The combined organiclayers were dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography eluting withDCM/MeOH=20/1˜10/1 to afford the title compoundN-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide(Example 2) as a yellow solid (800 mg, 70% yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 11.05 (s, 1H), 8.27 (s, 1H), 7.95 (dd,J=7.6 Hz, J=0.8 Hz, 1H), 7.86 (t, J=7.6 Hz, 1H), 7.45 (t, J=8.4 Hz, 1H),6.81-6.87 (m, 3H), 3.57 (s, 6H), 3.39 (q, J=7.2 Hz, 2H), 3.20 (s, 3H),1.03 (t, J=7.2 Hz, 3H). LC-MS: m/z 471.0 (M+H)⁺

Example 22:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)cyclopropanesulfonumide

The title compound was prepared according to Method C, step D, startingfromN-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamideby using cyclopropanesulfonamide (22 mg, 37% yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.25 (s, 1H), 8.02 (s, 1H), 7.86 (d, J=7.2Hz, 1H), 7.78 (t, J=7.6 Hz, 1H), 7.41 (t, J=8.4 Hz, 1H), 6.82 (d, J=8.4Hz, 2H), 6.72 (d, J=8.0 Hz, 1H), 3.55 (s, 6H), 3.37 (q, J=7.2 Hz 2H),2.52-2.54 (m, 1H), 1.01 (t, J=7.2 Hz, 3H), 0.79-0.83 (m, 2H), 0.64-0.69(m, 2H). LCMS: m/z 497.1 (M+H)⁺

Example 23:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)pyridine-2-sulfonamide

The title compound was prepared according to Method C, step D, startingfromN-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamideby using pyridine-2-sulfonamide (30 mg, 23% yield).

¹HNMR (400 MHz, DMSO-d₆) δ:11.77 (s, 1H), 8.55 (d, J=4.0 Hz, 1H), 8.21(s, 1H), 7.89 (d, J=7.6 Hz, 1H), 7.80 (t, J=7.6 Hz, 1H), 7.71 (d, J=7.6Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.49 (t, J=8.4 Hz, 2H), 6.86 (d, J=8.4Hz, 2H), 6.77 (d, J=8.0 Hz, 1H), 3.51 (s, 6H), 3.37 (q, J=7.2 Hz, 2H),1.01 (t, J=7.2 Hz, 3H). LC-MS: m/z 534 (M+H)⁺

Example 24:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)pyridine-3-sulfonamide

The title compound was prepared according to Method C, step D, startingfromN-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-y)-6-ethoxypicolinamideby using pyridine-3-sulfonamide (58 mg, 54% yield).

¹H NMR (400 MHz, DMSO-d₆) δ:11.81 (s, 1H), 8.79-8.90 (m, 1H), 8.65-8.78(m, 1H), 8.23 (s, 1H), 7.93 (t, J=8.4 Hz, 2H), 7.84 (t, J=8.0 Hz, 1H),7.55 (t, J=8.0 Hz, 1H), 7.37 (dd, J=8.0, 4.8 Hz, 1H), 6.93 (d, J=8.0 Hz,2H), 6.80-6.83 (m, 1H), 3.55 (s, 6H), 3.39 (q, J=7.1 Hz, 2H), 1.03 (t,J=7.1 Hz, 3H). LC-MS: m/z 534.0 (M+H)⁺

Example 25:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)pyridine-4-sulfonamide

The title compound was prepared according to Method C, step D, startingfromN-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamideby using pyridine-4-sulfonamide (45 mg, 57% yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.40 (s, 2H), 7.79-7.86 (m, 2H), 7.75 ((t,J=8.0 Hz, 1H), 7.53 (t, J=8.4 Hz, 1H), 7.43 (d, J=4.8 Hz, 2H), 6.93 (d,J=8.4 Hz, 2H), 6.69 (d, J=8.0 Hz, 1H), 3.53 (s, 6H), 3.38 (d, J=7.2 Hz,2H), 1.01 (t, J=7.2 Hz, 3H). LC-MS: m/z 534.0 (M+H)⁺

Example 26:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(pyridin-3-yl)methanesulfonamide

The title compound was prepared according to Method C, step D, startingfromN-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamideby using pyridin-3-ylmethanesulfonamide (24 mg, 25% yield).

¹H NMR (400 MHz, DMSO-d₆) δ:11.13 (s, 1H), 8.32-8.54 (m, 8.8 Hz, 2H),8.17 (s, 1H), 7.97 (dd, J=7.4, 0.9 Hz, 1H), 7.87 (dd, J=8.2, 7.6 Hz,1H), 7.44-7.5 (m, 2H), 7.38 (s, 1H), 6.89 (d, J=4.0 Hz, 2H), 6.84 (dd,J=4.0, 8.0 Hz, 3H), 4.72 (s, 2H), 3.58 (s, 6H), 3.40 (q, J=6.6 Hz, 2H),1.03 (t, J=7.2 Hz, 3H). LC-MS: m/z 548.0 (M+H)⁺

Example 27:N-(1-(2,6-dimethoxyphenyl-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-y)-1-(pyridin-2-yl)methanesulfonamide

The title compound was prepared according to Method C, step D, startingfromN-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamideby using pyridin-2-ylmethanesulfonamide (30 mg, 37% yield).

¹H NMR (400M, DMSO-d₆) δ: 11.12 (br, 1H), 8.45-8.47 (m, 1H), 8.14 (s,1H), 7.94 (dd, J=7.6 Hz, J=0.8 Hz, 1H), 7.86 (t, J=7.6 Hz, 1H), 7.75(td, J=7.6 Hz, J=1.6 Hz, 1H), 7.47 (t, J=8.4 Hz, 1H), 7.31-7.34 (m, 1H),7.2 (d, J=7.6 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.82 (dd, J=8.0 Hz, J=0.8Hz, 1H), 4.79 (s, 2H), 3.56 (s, 6H), 3.40 (q, J=7.2 Hz, 2H), 1.03 (t,J=7.2 Hz, 3H). LC-MS: m/z 548.6 (M+H)⁺

Step A: pyrimidin-2-ylmethanol

To a solution of methyl pyrimidine-2-carboxylate (25 g, 181 mmol, 1.0equiv) in MeOH (500 mL) was added NaBH₄ (8.2 g, 217 mmol, 1.2 equiv) at0° C. The reaction mixture was stirred at room temperature for 3 hours.The reaction mixture was quenched with H₂O (10 mL), concentrated invacuo and the residue was purified by flash column chromatography(PE/EtOAc=1/1) to afford the title compound pyrimidin-2-ylmethanol as ayellow oil (16 g, 80% yield).

LC-MS: m/z 111.0 (M+H)⁺

Step B: 2-((pyrimidin-2-ylmethyl)thio)benzo[d]thiazole

To a solution of pyrimidin-2-ylmethanol (16.6 g, 151 mmol, 1.0 equiv),benzo[d]thiazole-2-thiol (30 g, 181 mmol, 1.2 equiv) and PPh₃ (47.4 g,181 mmol, 1.2 equiv) in THF (500 mL) was added DEAD (36.6 g, 181 mmol,1.2 equiv) at 0° C. The mixture was stirred at room temperature for 16hours. The reaction mixture was quenched with HCl-dioxane and the whiteprecipitate was filtered off. The solid was then dissolved in 1N Na₂CO₃aqueous solution (100 mL) and extracted with EtOAc (3*200 mL). Thecombined organic phase was concentrated in vacuo to afford the titlecompound 2-((pyrimidin-2-ylmethyl)thio)benzo[d]thiazole as a crudeyellow solid (27 g, 77% yield).

LC-MS: m/z 260.0 (M+H)⁺

Step C: 2-((pyrimidin-2-ylmethyl)sulfonyl)benzo[d]thiazole

To a solution of 2-((pyrimidin-2-ylmethyl)thio)benzo[d]thiazole (27 g,104 mmol, 1.0 equiv) in DCM (500 mL) was added m-CPBA (51 g, 249 mmol,2.4 equiv). The mixture was stirred at room temperature for 16 hours andquenched with 1N Na₂SO₃ aqueous solution. The organic phase wasseparated, washed with saturated Na₂CO₃ and concentrated in vacuo. Theresidue was purified by flash column chromatography (PE/EtOAc=5/1) toafford the title compound2-((pyrimidin-2-ylmethyl)sulfonyl)benzo[d]thiazole as a white solid (17g, 80% yield).

LC-MS: m/z 292.0 (M+H)⁺

Step D: pyrimidin-2-ylmethanesulfonamide

To a solution of 2-((pyrimidin-2-ylmethyl)sulfonyl)benzo[d]thiazole (500mg, 1.7 mmol, 1.0 equiv) in MeOH (10 mL) was added K₂CO₃ (1.2 g, 8.5mmol, 5.0 equiv). After the mixture was stirred at room temperature for10 mins, NH₂OSO₃H (250 mg, 2.0 mmol, 1.2 equiv) in H₂O (1 mL) was added.The mixture was stirred at room temperature for 15 mins and anotherbatch of NH₂OSO₃H (250 mg, 2.0 mmol, 1.2 equiv) in H₂O (1 mL) was added.The resulting mixture was stirred at room temperature for 60 hours. Themixture was evaporated and the residue was purified by flash columnchromatography (DCM/MeOH=50/1) to afford the title compoundpyrimidin-2-ylmethanesulfonamide as a white solid (100 mg, 34% yield).

¹H NMR (400 MHz, DMSO) δ 8.83 (d, J=4.8 Hz, 2H), 7.49 (t, J=4.8 Hz, 1H),7.01 (s, 2H), 4.55 (s, 2H). LC-MS: m/z 174.0 (M+H)⁺

Example 28:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(pyrimidin-2-yl)methanesulfonamide

The title compound was prepared according to Method C, step D, startingfromN-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamideby using pyrimidin-2-ylmethanesulfonamide (27 mg, 34% yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 11.19 (s, 1H), 8.74 (d, J=4.8 Hz, 2H), 8.21(s, 1H), 7.94 (d, J=7.2 Hz, 1H), 7.86 (t, J=8.0 Hz, 1H), 7.40-7.49 (m,2H), 6.85 (d, J=8.4 Hz, 2H), 6.82 (dd, J=8.2, 0.8 Hz, 1H), 3.55 (s, 6H),3.39 (q, J=7.2 Hz, 2H), 1.02 (t, J=7.2 Hz, 3H). LCMS: m/z 548.9 (M+H)⁺

2-cyclopropylethanesulfonamide

The title compound was prepared according to the preparation ofpyrimidin-2-ylmethanesulfonamide by using 2-cyclopropylethanol in stepA.

LC-MS: m/z 150.2 (M+H)⁺

Example 29:2-cyclopropyl-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)ethanesulfonamide

The title compound was prepared according to Method C, step D, startingfrom6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(Example 1) by using 2-cyclopropylethanesulfonamide (50 mg, 47% yield).

¹H NMR (400M, DMSO-d₆) δ:10.98 (br, 1H), 8.27 (s, 1H), 7.95 (d, J=7.2Hz, 1H), 7.85 (t, J=8.4 Hz, 1H), 7.45 (t, J=8.4 Hz, 1H), 6.86 (d, J=8.4Hz, 2H), 6.82 (d, J=8.4 Hz, 1H), 3.58 (s, 6H), 3.36-3.42 (m, 4H),1.47-1.52 (m, 2H), 1.03 (t, J=7.2 Hz, 3H), 0.63-0.68 (m, 1H), 0.29-0.33(m, 2H), 0.06-0.1 (m, 2H). LC-MS: m/z 525.4 (M+H)⁺

oxetane-3-sulfonamide

The title compound was prepared according to the preparation ofpyrimidin-2-ylmethanesulfonamide by using oxetan-3-ol in step A.

¹H NMR (400 MHz, DMSO) δ: 7.17 (s, 2H), 4.79 (dd, J=8.0, 7.2 Hz, 2H),4.68-4.65 (m, 2H), 4.47-4.40 (m, 1H).

Example 30:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)oxetane-3-sulfonamide

The title compound was prepared according to Method C, step D, startingfromN-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamideby using oxetane-3-sulfonamide (36.3 mg, 35% yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.05 (s, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.81(t, J=7.6 Hz, 1H), 7.43 (t, J=8.4 Hz, 1H), 6.86 (d, J=8.4 Hz, 2H), 6.76(d, J=8.0 Hz, 1H), 4.49-4.67 (m, 3H), 4.34 (t, J=6.6 Hz, 2H), 3.60 (s,6H), 3.38 (q, J=7.2 Hz, 2H), 1.02 (t, J=7.2 Hz, 3H). LC-MS: m/z 513.1(M+H)⁺

Step A: 2-(cyclobutylthio)pyrimidine

To a solution of PPh₃ (4.37 g, 16.7 mmol, 1.2 equiv) in THF (30 mL) at0° C. was added DIAD (3.37 g, 16.7 mmol, 1.2 equiv) dropwise under N₂atmosphere. After the mixture was stirred at 0° C. for 10 mins, amixture of pyrimidine-2-thiol (1.867 g, 16.7 mmol, 1.2 equiv) andcyclobutanol (1.0 g, 13.9 mmol, 1.0 equiv) in THF (10 mL) was added. Theresulting mixture was stirred at 0° C. for 10 mins and at roomtemperature for 1 h. The reaction solution was concentrated and theresidue was purified by flash column chromatography (PE/EtOAc=6/1) toafford the desired 2-(cyclobutylthio)pyrimidine as a yellow oil (2.0 g,87% yield).

LC-MS: m/z 167.0 (M+H)⁺

Step B: 2-(cyclobutylsulfonyl)pyrimidine

To a solution of m-CPBA (5.7 g, 33.1 mmol, 3 equiv) in DCM (80 mL) wasadded 2-(cyclobutylthio)pyrimidine (1.83 g, 11.0 mmol, 1.0 equiv). Thereaction mixture was stirred at room temperature for 16 h. SaturatedNa₂S₂O₃ aqueous solution (20 mL) was added and the mixture was stirredat room temperature for 30 mins. The organic phase was separated andwashed with brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by flash column chromatography(PE/EtOAc=1/1) to afford the title compound2-(cyclobutylsulfonyl)pyrimidine as a yellow solid (1.7 g, 78% yield).

LC-MS: m/z 199.0 (M+H)⁺

Step C: cyclobutanesulfonamide

To a solution of 2-(cyclobutylsulfonyl)pyrimidine (1.75 g, 8.84 mmol,1.0 equiv) in MeOH (40 mL) was added NaOMe (5.4 mol/L, 1.64 mL, 1.0equiv). After the reaction mixture was stirred at 0° C. for 30 mins, asolution of NaOAc (906 mg, 11.05 mmol, 1.25 equiv) and HOSO₃NH₂ (1.25 g,11.05 mmol, 1.25 equiv) in water (5 mL) was added. The resulting mixturewas stirred at room temperature for 16 h. The reaction suspension wasfiltered and the filtrate was concentrated in vacuo. The residue waspurified by flash column chromatography (PE/EtOAc=1/1) to afford thetitle compound cyclobutanesulfonamide as a white solid (300 mg, 25%yield).

LC-MS: m/z 136.0 (M+H)⁺

Example 31:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)cyclobutanesulfonamide

The title compound was prepared according to Method C, step D, startingfromN-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamideby using cyclobutanesulfonamide (85 mg, 64% yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 10.87 (s, 1H), 8.31 (s, 1H), 7.95 (dd,J=7.4, 0.8 Hz, 1H), 7.86 (dd, J=8.4, 7.6 Hz, 1H), 7.46 (t, J=8.4 Hz,1H), 6.87 (d, J=8.4 Hz, 2H), 6.83 (dd, J=8.4, 0.8 Hz, 1H), 4.09-4.22 (m,1H), 3.59 (s, 6H), 3.39 (q, J=7.2 Hz, 2H), 2.28 (ddt, J=13.0, 10.6, 8.6Hz, 2H), 2.02-2.13 (m, 2H), 1.75-1.92 (m, 2H), 1.03 (t, J=7.2 Hz, 3H).LC-MS: m/z 511.2 (M+H)⁺

Example 32:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-N-methylmethanesulfonamide

The title compound was prepared according to Method C, step D, startingfrom6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(Example 1) by using N-methylmethanesulfonamide (40 mg, 75% yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.63 (s, 1H), 7.98 (t, J=7.2 Hz, 1H), 7.89(t, J=8.4 Hz, 1H), 7.47 (t, J=8.4 Hz, 1H), 6.87 (d, J=8.4 Hz, 2H), 6.86(d, J=8.4 Hz, 2H), 3.57 (s, 6H), 3.41 (q, J=7.2 Hz, 2H), 3.26 (s, 3H),3.12 (s, 3H), 1.03 (t, J=7.2 Hz, 3H). LC-MS: m/z 485.2 (M+H)⁺

Trans-3-(benzyloxy)cyclobutane-1-sulfonamide

The title compound was prepared according to the preparation ofcyclobutanesulfonamide by using cis-3-(benzyloxy)cyclobutanol in step A.

¹H NMR (400 MHz, DMSO-d₆) δ: 7.27-7.37 (m, 5H), 6.83 (s, 2H), 4.38 (s,2H), 4.18-4.24 (m, 1H), 3.57-3.64 (m, 1H), 2.49-2.58 (m, 2H), 2.28-2.36(m, 2H).

trans-3-(benzyloxy)-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)cyclobutane-1-sulfonamide

The title compound was prepared according to Method C, step D, startingfromN-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamideby using trans-3-(benzyloxy)cyclobutane-1-sulfonamide (460 mg, 48%yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 11.00 (s, 1H), 8.23 (s, 1H), 7.94-7.96 (m,1H), 7.85 (t, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.27-7.28 (m, 5H),6.81-6.84 (m, 3H), 4.35 (s, 2H), 4.07-4.19 (m, 2H), 3.57 (s, 6H),3.36-3.41 (m, 2H), 2.54-2.60 (m, 2H), 2.19-2.26 (m, 2H), 1.02 (t, J=8.0Hz, 3H). LC-MS: m/z 617.0 (M+H)⁺

Example 33:cis-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-3-hydroxycyclobutane-1-sulfonamide

To a mixture oftrans-3-(benzyloxy)-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)cyclobutane-1-sulfonamide(200 mg, 0.324 mmol, 1.0 equiv) in DCM (16 mL) were addedtrifluoromethanesulfonic acid (1 mL) and trifluoromethanesulfonicanhydride (0.5 mL) at 0° C. under N₂ atmosphere. The resulting mixturewas stirred at 0° C. for 15 minutes under N₂ atmosphere. Then themixture was adjusted to pH=6 by adding aqueous NaHCO₃ (3 mol/L) and DCM(60 mL) was added into the mixture. The combined organic layers werewashed with brine (20 mL), dried over Na₂SO₄, filtered and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluting with DCM/MeOH=20/1˜10/1) to afford the titlecompound as a brown solid (50 mg, 29% yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.19 (s, 1H), 7.90 (d, J=7.2 Hz, 1H), 7.82(t, J=7.6 Hz, 1H), 7.43 (t, J=8.4 Hz, 1H), 6.84 (d, J=8.8 Hz, 2H), 6.77(d, J=8.4 Hz, 1H), 5.22 (s, 1H), 4.20-4.33 (m, 1H), 3.93-3.98 (m, 1H),3.59 (s, 6H), 3.39 (q, J=7.2 Hz, 2H), 2.42-2.50 (m, 2H), 1.97-2.12 (m,2H), 1.02 (t, J=7.2 Hz, 3H). LC-MS: m/z 527.2 (M+H)⁺

Step B:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-3-oxocyclobutane-1-sulfonamide

The solution ofcis-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-3-hydroxycyclobutane-1-sulfonamide(Example 33, 60 mg, 0.114 mmol, 1.0 equiv) in DCM (2 mL) was cooled to0° C. and Dess-Matin periodinane (193 mg, 0.456 mmol, 4 equiv) wasadded. The mixture was stirred at room temperature overnight. Themixture was washed with Na₂SO₃ (aq.) brine, dried over Na₂SO₄, andconcentrated in vacuo. The residue was purified by prep-TLC to giveN-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-3-oxocyclobutane-1-sulfonamideas a light yellow solid (50 mg, 83% yield).

LC-MS: m/z 525.2 (M+H)⁺

Example 34:trans-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-3-hydroxycyclobutane-1-sulfonamide

The solution ofN-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-3-oxocyclobutane-1-sulfonamide(50 mg, 0.095 mmol, 1.0 equiv) in MeOH (1 mL) was cooled to 0° C. andNaBH₄ (7.2 mg, 0.191 mmol, 3.0 equiv) was added. The mixture was allowedto be warmed to room temperature and stirred for 2 h. After that, H₂O (1mL) was added and the mixture was extracted with DCM three times. Thecombined organic layers were washed with brine, concentrated andpurified via prep-TLC to give the title compound as a white solid (22mg, 44% yield).

¹H NMR (400 MHz, CDCl₃) δ: 8.48 (s, 1H), 8.04 (d, J=7.6 Hz, 1H), 7.60(t, J=7.6 Hz, 1H), 7.30 (t, J=8.4 Hz, 1H), 6.76 (s, 1H), 6.61-6.65 (m,3H), 4.01-4.06 (m, 1H), 3.55 (s, 6H), 3.44-3.50 (m, 1H), 3.32-3.38 (m,2H), 2.50-2.54 (m, 2H), 2.26-2.32 (m, 2H), 1.02 (t, J=7.2 Hz, 3H).LC-MS: m/z 527.2 (M+H)⁺

pyrimidin-5-ylmethanesulfonamide

The title compound was prepared according to the preparation ofcyclobutanesulfonamide by using pyrimidin-5-ylmethanol in step A.

¹H NMR (400 MHz, DMSO-d₆) δ: 9.17 (s, 1H), 8.77 (s, 2H), 7.03 (br. s,2H), 4.38 (s, 2H). LC-MS: m/z 174.0 (M+H)⁺

Example 35:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(pyrimidin-5-yl)methanesulfonamide

The title compound was prepared according to Method C, step D, startingfromN-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamideby using pyrimidin-5-ylmethanesulfonamide.

¹H NMR (400 MHz, DMSO-d₆) δ: 11.20 (s, 1H), 9.15 (s, 1H), 8.54 (s, 2H),8.27 (s, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.87 (t, J=7.6 Hz, 1H), 7.48 (t,J=8.4 Hz, 1H), 6.89 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.0 Hz, 1H), 4.74 (s,2H), 3.60 (s, 6H), 3.41 (q, J=7.2 Hz, 2H), 1.03 (t, J=7.2 Hz, 3H).LC-MS: m/z 549.2 (M+H)⁺

Step A: tetrahydro-2H-pyran-4-sulfonamide

To a solution of tetrahydro-2H-pyran-4-sulfonyl chloride (300 mg, 1.6mmol, 1.6 equiv) in acetone (5 mL) was added aqueous NH₄OH (34% wt., 10mL, 140 mmol, 88 equiv). The mixture was stirred at room temperatureovernight and then concentrated to dryness. The residue was purified bysilica gel column chromatography (DCM/EtOAc=2/1) to afford the titlecompound tetrahydro-2H-pyran-4-sulfonamide as a white solid (150 mg, 56%yield).

LC-MS: m/z 166.2 (M+H)⁺

Example 36:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)tetrahydro-2H-pyran-4-sulfonamide

The title compound was prepared according to Method C, step D, startingfromN-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamideby using tetrahydro-2H-pyran-4-sulfonamide (25 mg, 32% yield).

¹H NMR (DMSO-d₆) δ:10.93-11.20 (m, 1H), 8.28 (s, 1H), 7.96 (d, J=8.0 Hz,1H), 7.85 (t, J=8.0 Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 6.88 (d, J=8.8 Hz,2H), 6.82 (d, J=8.0 Hz, 1H), 3.87-3.91 (m, 2H), 3.58 (s, 7H), 3.39 (q,J=7.2 Hz, 2H), 3.07 (t, J=11.2 Hz, 2H), 1.75-1.78 (m, 2H), 1.55-1.66 (m,2H), 1.02 (t, J=7.2 Hz, 3H). LC-MS: m/z 541.6 (M+H)⁺

morpholine-4-sulfonamide

The title compound was prepared according to the preparation oftetrahydro-2H-pyran-4-sulfonamide by using morpholine-4-sulfonylchloride.

¹H NMR (400 MHz, de-DMSO) δ: 6.82 (s, 2H), 3.61-3.68 (m, 4H), 2.89-2.94(m, 4H).

Example 37:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)morpholine-4-sulfonamide

The title compound was prepared according to Method C, step D, startingfrom6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(Example 1) by using morpholine-4-sulfonamide (39 mg, 65% yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 11.03 (s, 1H), 8.24 (s, 1H), 7.97 (dd,J=7.4, 0.8 Hz, 1H), 7.85 (dd, J=8.2, 7.6 Hz, 1H), 7.45 (t, J=8.4 Hz,1H), 6.86 (d, J=8.4 Hz, 2H), 6.82 (dd, J=8.2, 0.8 Hz, 1H), 3.60 (s, 6H),3.42-3.46 (m, 4H), 3.38 (q, J=7.2 Hz, 2H), 2.90-2.95 (m, 4H), 1.02 (t,J=7.2 Hz, 3H). LC-MS: m/z 543.1 (M+H)⁺

benzyl 4-(sulfamoylmethyl)piperidine-1-carboxylate

The title compound was prepared according to the preparation oftetrahydro-2H-pyran-4-sulfonamide by using benzyl4-((chlorosulfonyl)methyl)piperidine-1-carboxylate (350 mg, 56% yield).

LC-MS: m/z 313.1 (M+H)⁺.

benzyl-4-((N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)sulfamoyl)methyl)piperidine-1-carboxylate

The title compound was prepared according to Method C, step D, startingfromN-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamideby using benzyl 4-(sulfamoylmethyl)piperidine-1-carboxylate (210 mg, 45%yield).

LC-MS: m/z 688.2 (M+H)⁺

Example 38:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-y)-1-(piperidin-4-yl)methanesulfonamide

A solution ofbenzyl-4-((N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)sulfamoyl)methyl)piperidine-1-carboxylate(55 g, 0.08 mmol, 1.0 equiv) and con. HCl (1 mL) in EtOH (4 mL) wasrefluxed at 90° C. for 8 h. The reaction mixture was concentrated andresidue was purified by flash column chromatography on silica gel(DCM/MeOH=10/1) to give the title compound as a yellow solid (40 mg, 90%yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.23 (s, 1H), 7.81-7.83 (m, 2H), 7.74-7.77(m, 1H), 7.38 (t, J=8.0 Hz, 1H), 6.81 (d, J=8.0 Hz, 2H), 6.68 (d, J=8.0Hz, 1H), 3.57 (s, 6H), 3.36 (q, J=7.2 Hz, 2H), 3.11-3.14 (m, 2H),2.95-2.96 (m, 2H), 2.76-2.82 (m, 2H), 1.94 (s, 1H), 1.81-1.84 (m, 2H),1.18-1.27 (m, 2H), 1.01 (t, J=7.2 Hz, 3H). LC-MS: m/z 554.2 (M+H)⁺.

4-oxocyclohexane-1-sulfonamide

The title compound was prepared according to the preparation oftetrahydro-2H-pyran-4-sulfonamide by using 4-oxocyclohexane-1-sulfonylchloride (150 mg, 56% yield).

LC-MS: m/z 178.0 (M+H)⁺

N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-4-oxocyclohexane-1-sulfonamide

The title compound was prepared according to Method C, step D, startingfromN-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamideby using 4-oxocyclohexane-1-sulfonamide (140 mg, 69% yield).

LC-MS: m/z 553.2 (M+H)⁺

Example 39:trans-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-4-hydroxycyclohexane-1-sulfonamideExample 40:cis-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-4-hydroxycyclohexane-1-sulfonamide

To a solution ofN-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-4-oxocyclohexane-1-sulfonamide(135 mg, 0.244 mmol, 1.0 equiv) in MeOH (10 mL) was added NaBH₄ (18.6mg, 0.49 mmol, 3.0 equiv). The mixture was stirred at 0° C. for 30 minsand at room temperature for 3 h. The reaction solution was quenched with1N HCl (25 mL), extracted with DCM (3*25 mL). The combined organic phasewas washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by prep-TLC (DCM/MeOH=10/1) togive Example 39 (50 mg, 37% yield) and Example 40 (12 mg, 9% yield) aswhite solid.

Example 39: ¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (s, 1H), 8.31 (s, 1H),7.97 (dd, J=7.4, 0.8 Hz, 1H), 7.86 (dd, J=8.2, 7.5 Hz, 1H), 7.46 (t,J=8.4 Hz, 1H), 6.77-6.98 (m, 3H), 4.66 (d, J=4.2 Hz, 1H), 3.59 (s, 6H),3.40 (q, J=7.2 Hz, 2H), 3.30 (q, J=3.4, 2.8 Hz, 1H), 2.44-2.50 (m, 1H),1.88 (dd, J=24.0, 12.8 Hz, 4H), 1.39-1.50 (m, 2H), 1.03 (t, J=7.2 Hz,3H), 0.96 (dd, J=13.2, 10.0 Hz, 2H). LC-MS: m/z 555.2 (M+H)⁺

Example 40: ¹H NMR (400 MHz, DMSO-d₆) δ 10.86 (s, 1H), 8.31 (s, 1H),7.97 (dd, J=7.4, 0.8 Hz, 1H), 7.86 (dd, J=8.4, 7.6 Hz, 1H), 7.45 (t,J=8.4 Hz, 1H), 6.87 (d, J=8.4 Hz, 2H), 6.83 (dd, J=8.2, 0.8 Hz, 1H),4.43 (d, J=2.8 Hz, 1H), 3.76 (d, J=5.6 Hz, 1H), 3.58 (s, 6H), 3.39 (q,J=7.2 Hz, 3H), 1.81 (q, J=14.0, 12.6 Hz, 2H), 1.59-1.74 (m, 4H), 1.19(d, J=12.0 Hz, 2H), 1.02 (t, J=7.2 Hz, 3H). LC-MS: m/z 555.2 (M+H)⁺

Step A: pyrimidine-2-sulfonyl chloride

Sodium hypochlorite (30.9 mL, 60.0 mmol) was added dropwise with rapidstirring to a solution of 2-mercaptopyrimidine (1.1 g, 10 mmol) inCH₂Cl₂ (60 mL) and 1N HCl (55.0 mL, 55.0 mmol) at −20° C. After theaddition was completed, the mixture was stirred at −20° C. for 15 mins.The organic layer was separated and used directly for next step.

Step B: pyrimidine-2-sulfonamide

The solution of pyrimidine-2-sulfonyl chloride in CH₂Cl₂ (60 mL) wasadded to NH₄OH (aq., 34%, 60 mL) at 0° C. and the mixture was slowlyallowed to warm to room temperature and stirred for 1 h. The mixture wasconcentrated under vacuum, residue was purified by silica gelchromatography (CH₂Cl₂/MeOH=20/1) to afford the title compoundpyrimidine-2-sulfonamide as a light yellow solid (350 mg, 1.98 mmol, 20%yield in two steps).

LC-MS: m/z 160.0 (M+H)⁺

Example 41:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)pyrimidine-2-sulfonamide

The title compound was prepared according to Method C, step D, startingfrom6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(Example 1) by using pyrimidine-2-sulfonamide (55 mg, 70%/yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 11.91 (s, 1H), 8.82 (d, J=4.8 Hz, 2H), 8.35(s, 1H), 7.92 (d, J=7.6 Hz, 1H), 7.83 (t, J=7.6 Hz, 1H), 7.67 (t, J=4.8Hz, 1H), 7.41 (t, J=8.4 Hz, 1H), 6.78 (dd, J=11.4, 8.4 Hz, 3H), 3.50 (s,6H), 3.35 (d, J=7.2 Hz, 2H), 1.00 (t, J=7.2 Hz, 3H). LC-MS: m/z 534.1(M+H)⁺

Step A: 4-hydroxypiperidine-1-sulfonamide

A mixture of piperidin-4-ol (1.0 g, 10 mmol, 1.0 equiv) and sulfuricdiamide (960 mg, 10 mmol, 1.0 equiv) in dioxane (20 mL) was stirred at120° C. for 16 h. After evaporation, the residue was purified by flashcolumn chromatography (eluting with DCM/MeOH=10/1) to afford the titlecompound 4-hydroxypiperidine-1-sulfonamide as a white solid, (1.09 g,61% yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 6.67 (s, 2H), 4.70 (d, J=3.6 Hz, 1H),3.54-3.61 (m, 1H), 3.18-3.24 (m, 2H), 2.70-2.76 (m, 2H), 1.73-1.78 (m,2H), 1.41-1.49 (m, 2H).

Example 42:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-4-hydroxypiperidine-1-sulfonamide

The title compound was prepared according to Method C, step D, startingfromN-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamideby using 4-hydroxypiperidine-1-sulfonamide (34.5 mg, 31% yield).

¹H NMR (400 MHz, CDCl₃) δ 8.38 (s, 1H), 8.11 (d, J=7.2 Hz, 1H),7.65-7.69 (m, 1H), 7.35-7.40 (m, 1H), 7.18 (s, 1H), 6.67-6.70 (m, 3H),3.67-3.73 (m, 1H), 3.63 (s, 6H), 3.39-3.49 (m, 4H), 2.96-3.03 (m, 2H),1.74-1.81 (m, 2H), 1.44-1.53 (m, 2H), 1.08 (t, J=7.2 Hz, 3H). LC-MS: m/z555.9 (M+H)⁺

Method D:

Example 43:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)methanesulfonamide

The title compound was prepared according to Method C, step D, startingfrom5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(Example 15) by using methanesulfonamide (26 mg, 23% yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 11.11 (s, 1H), 7.98 (d, J=6.8 Hz, 1H), 7.95(s, 1H), 7.86 (t, J=7.6 Hz, 1H), 7.45 (t, J=8.4 Hz, 1H), 6.85 (d, J=8.4Hz, 2H), 6.82 (dd, J=8.2, 0.4 Hz, 1H), 3.58 (s, 6H), 3.39 (q, J=7.2 Hz,2H), 3.36 (s, 3H), 1.03 (t, J=7.2 Hz, 3H). LCMS: m/z 471.0 (M+H)⁺

Example 44:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)methanesulfonamide

The title compound was prepared according to Method C, step D, startingfrom5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(Example 15) by using 2-cyclopropylethanesulfonamide (30 mg, 16% yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 7.98-8.00 (m, 2H), 7.86 (t, J=8.0 Hz, 1H),7.45 (t, J=8.4 Hz, 1H), 6.82-6.88 (m, 3H), 3.61-3.66 (m, 2H), 3.56 (s,6H), 3.39 (q, J=7.2 Hz, 2H), 1.57-1.67 (m, 2H), 1.03 (t, J=7.2 Hz, 3H),0.92-0.82 (m, 1H), 0.46-0.38 (m, 2H), 0.09 (q, J=4.8 Hz, 2H). LCMS: m/z525.35 (M+H)⁺

Example 45:1-cyclopropyl-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)methanesulfonamide

The title compound was prepared according to Method C, step D, startingfrom5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(Example 15) by using cyclopropylmethanesulfonamide (20 mg, 32% yield).¹H NMR (400 MHz, DMSO-d₆) δ: 10.95 (s, 1H), 8.06 (s, 1H), 7.98-8.00 (m,1H), 7.87 (t, J=8.0 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 6.83-6.88 (m, 3H),3.58 (s, 6H), 3.55 (d, J=8.0 Hz, 2H), 3.39 (q, J=7.2 Hz, 2H), 1.09-1.14(m, 1H), 1.03 (t, J=7.2 Hz, 3H), 0.59-0.61 (m, 2H), 0.36-0.37 (m, 2H).LC-MS: m/z 511.0 (M+H)⁺.

Example 46:1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-N-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyrazin-5-amine

The mixture of5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(Example 15, 100 mg, 0.24 mmol, 1.0 equiv), PMBNH₂ (67 mg, 0.48 mmol,2.0 equiv), Xantphos (29 mg, 0.048 mmol, 0.2 equiv), Pd₂(dba)₃ (23 mg,0.024 mmol, 0.1 equiv), ^(t)BuOK (55 mg, 0.48 mmol, 2.0 equiv) intoluene (5 mL) was stirred at 110° C. for 16 hours under N₂ atmosphere.The mixture was filtered and the filtrate was concentrated in vacuo. Theresidue was purified by flash chromatography on silica gel(PE/EtOAc=10/1˜1/1) to afford the title compound as a yellow solid (30mg, 24% yield).

¹H NMR (400 MHz, DMSO) δ: 7.87 (d, J=7.2 Hz, 1H), 7.79 (t, J=7.6 Hz,1H), 7.72 (s, 1H), 7.49 (t, J=5.6 Hz, 1H), 7.41 (t, J=8.4 Hz, 1H), 7.33(d, J=8.4 Hz, 2H), 6.90 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.4 Hz, 2H), 6.74(d, J=7.6 Hz, 1H), 4.48 (d, J=5.6 Hz, 2H), 3.73 (s, 3H), 3.57 (s, 6H),3.36 (q, J=7.2 Hz, 2H), 1.01 (t, J=7.2 Hz, 3H). LCMS: m/z 513.2 (M+H)⁺

Method E:

Step A:N-(5-chloro-3-((2-methoxy-6-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide

A suspension of N-(3-bromo-5-chloropyrazin-2-yl)-6-ethoxypicolinamide(100 mg, 0.28 mmol, 1.0 equiv), 2-methoxy-6-(trifluoromethyl)aniline(53.5 mg, 0.28 mmol, 1.0 equiv), Pd₂(dba)₃ (102 mg, 0.11 mmol, 0.4equiv), Xantphos (130 mg, 0.22 mmol, 0.8 equiv) and K₂CO₃ (77 mg, 0.56mmol, 2.0 equiv) in 1,4-dioxane (2 mL) was stirred at 130° C. viamicrowave irradiation for 2 hours under N₂ atmosphere. The mixture wasfiltered through celite and the filtrate was concentrated in vacuo. Theresidue was purified by flash chromatography (eluting with EtOAc/PE=1/6)to afford the title compoundN-(5-chloro-3-((2-methoxy-6-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamideas a yellow solid (2 mg, 2% yield) and byproduct2-(6-ethoxypyridin-2-yl)-1-(2-methoxy-6-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyrazin-6-ol(Example 47, 22 mg, 18% yield).

LC-MS: m/z 468.1 (M+H)⁺

Example 47:2-(6-ethoxypyridin-2-yl)-1-(2-methoxy-6-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyrazin-6-ol

¹H NMR (400 MHz, DMSO-d₆) δ: 9.28 (s, 1H), 8.17 (s, 1H), 7.91 (dd,J=8.2, 7.6 Hz, 1H), 7.84 (dd, J=7.6, 0.8 Hz, 1H), 7.57 (t, J=8.0 Hz,1H), 7.49 (dd, J=8.4, 1.6 Hz, 1H), 7.40 (dd, J=8.0, 1.6 Hz, 1H), 7.00(dd, J=8.4, 0.8 Hz, 1H), 4.41 (q, J=7.2 Hz, 2H), 3.76 (s, 3H), 1.35 (t,J=7.2 Hz, 3H). LC-MS: m/z 432.1 (M+H)⁺

Step B:6-chloro-2-(6-ethoxypyridin-2-yl)-1-(2-methoxy-6-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyrazine

A solution ofN-(5-chloro-3-((2-methoxy-6-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide(35 mg, 0.075 mmol) in AcOH (2 mL) was stirred at 130° C. via microwaveirradiation for 2 hours. The mixture was concentrated and the residuewas purified by prep-TLC to afford the title compound6-chloro-2-(6-ethoxypyridin-2-yl)-1-(2-methoxy-6-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyrazineas a yellow solid (25 mg, 74% yield).

LC-MS: m/z 450.0 (M+H)⁺

Example 48:N-(2-(6-ethoxypyridin-2-yl)-1-(2-methoxy-6-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

A suspension of6-chloro-2-(6-ethoxypyridin-2-yl)-1-(2-methoxy-6-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyrazine(25 mg, 0.056 mmol), Methanesulfonamide (11 mg, 0.112 mmol, 2 equiv),CuI (21 mg, 0.112 mmol, 2 equiv),trans-N,N′-Dimethylcyclohexane-1,2-diamine (16 mg, 0.112 mmol, 2 equiv)and K₂CO₃ (23 mg, 0.167 mmol, 3 equiv) in DMF (2 mL) was stirred at 130°C. via microwave irradiation for 2 hours under N₂ atmosphere. Themixture was diluted with EtOAc (30 mL) and filtered through celite. Thefiltrate was poured into aqueous K₂CO₃ (2 mol/L, 50 mL), stirred for 15mins. Then the aqueous phase was separated and washed by EtOAc (2*30mL). The aqueous phase was adjusted to pH=3 with 1N HCl and extractedwith DCM (3*100 mL). The combined organic layers were washed with brine,dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash chromatography (eluting with DCM/MeOH=20/1˜10/1) toafford the title compound as a white solid. (10 mg, 35% yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 11.13 (s, 1H), 8.32 (s, 1H), 8.06 (dd,J=7.4, 0.8 Hz, 1H), 7.88 (dd, J=8.4, 7.6 Hz, 1H), 7.74-7.83 (m, 1H),7.61-7.70 (m, 1H), 7.56 (dd, J=8.0, 1.2 Hz, 1H), 6.85 (dd, J=8.4, 0.8Hz, 1H), 3.65 (s, 3H), 3.22 (q, J=7.2 Hz, 2H), 3.12 (s, 3H), 1.00 (t,J=7.2 Hz, 3H). LC-MS: m/z 509.1 (M+H)⁺

Example 49:N-(2-(6-ethoxypyridin-2-yl)-1-(3-methoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

The title compound was prepared according to Method E by using3-methoxypyridin-2-amine in step A.

¹H NMR (400 MHz, CDCl₃) δ: 8.55 (s, 1H), 8.25 (dd, J=4.8, 1.2 Hz, 1H),8.15 (d, J=4.0 Hz, 1H), 7.71 (t, J=8.0 Hz, 1H), 7.45-7.48 (m, 1H),7.39-7.41 (m, 1H), 7.15 (s, 1H), 6.72 (d, J=8.0 Hz, 1H), 3.66 (s, 3H),3.35-3.40 (m, 2H), 3.17 (s, 3H), 1.08 (t, J=8.0 Hz, 3H). LC-MS: m/z442.0 (M+H)⁺.

Example 50:N-(benzylsulfonyl)-4-(2-fluoro-6-methoxyphenyl)-5-(6-methoxypyridin-2-yl)-4H-1,2,4-triazole-3-carboxamide

The title compound was prepared according to Method E by using2-fluoro-6-methoxyaniline in step A.

¹H NMR (400 MHz, DMSO-d₆) δ: 11.17 (s, 1H), 8.31 (s, 1H), 7.99 (d, J=7.6Hz, 1H), 7.89 (t, J=7.6 Hz, 1H), 7.56 (dd, J=15.2, 8.4 Hz, 1H),7.05-7.18 (m, 2H), 6.87 (d, J=8.4 Hz, 1H), 3.61 (s, 3H), 3.41 (q, J=7.2Hz, 2H), 3.19 (s, 3H), 1.04 (t, J=7.2 Hz, 3H). LC-MS: m/z 459.1 (M+H)⁺

Method F:

Step A: N-(3,5-dibromopyrazin-2-yl)-6-methoxypicolinamide

To a solution of 3,5-dibromopyrazin-2-amine (13.6 g, 54 mmol, 1.3 equiv)in THF was added AlMe₃ (1.6 mol/L, 34 mL, 54 mmol, 1.3 equiv) dropwiseat room temperature under argon atmosphere. The mixture was stirred atroom temperature for 0.5 h. Then 3,5-dibromopyrazin-2-amine (6.8 g., 41mmol, 1.0 equiv) was added in one portion. The mixture was stirred at60° C. for 1.5 h, quenched with 1N HCl (aq.) and extracted with ethylacetate for three times. The extracts were washed with brine, dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel to afford the title compoundN-(3,5-dibromopyrazin-2-yl)-6-methoxypicolinamide as a yellow solid (14g, 88.1% yield).

LC-MS: m/z 386.8, 388.8, 390.8 (M+H)⁺

Step B:N-(5-bromo-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-methoxypicolinamide

A suspension of N-(3,5-dibromopyrazin-2-yl)-6-methoxypicolinamide (600mg, 1.54 mmol, 1.0 equiv), 2,6-dimethoxyaniline (236 mg, 1.54 mmol, 1.0equiv), Pd(OAc)₂ (70 mg, 0.31 mmol, 0.2 equiv), Xantphos (358 mg, 0.62mmol, 0.4 equiv) and K₂CO₃ (440 mg, 3.1 mmol, 2.0 equiv) in 1,4-dioxane(10 mL) was stirred at 120° C. via microwave irradiation for 2 hourunder N₂ atmosphere. The mixture was filtered through celite and thefiltrate was concentrated in vacuo. The residue was purified by flashcolumn chromatography (PE/EtOAc=4/1) to afford the desired productN-(5-bromo-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-methoxypicolinamide(70 mg, 10% yield).

LC-MS: m/z 459.9, 461.9 (M+H)⁺

Step C:6-bromo-1-(2,6-dimethoxyphenyl-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine

A solution ofN-(5-bromo-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-methoxypicolinamide(700 mg, 1.53 mmol) in AcOH (10 mL) was stirred at 120° C. via microwaveirradiation for 2 hour. The reaction mixture was concentrated in vacuoand the residue was purified by column chromatography to give thedesired product6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineas a light yellow solid (475 mg, 70%).

LC-MS: m/z 442.3, 444.3 (M+H)⁺

Example 51:N-(1-(2,6-dimethoxyphenyl)-2-(6-methoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

The title compound was prepared according to Method F by usingmethanesulfonamide in step D (72 mg, 78% yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 11.05 (s, 1H), 8.30 (s, 1H), 7.95 (d, J=8.0Hz, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 6.85 (d, J=8.0Hz, 3H), 3.57 (s, 6H), 3.20 (s, 3H), 3.11 (s, 3H). LC-MS: m/z 457.0(M+H)⁺

Example 52:N-(1-(2,6-dimethoxyphenyl)-2-(6-methoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)pyridine-2-sulfonamide

The title compound was prepared according to Method F by usingpyridine-2-sulfonamide in step D (34 mg, 33% yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 11.77 (s, 1H), 8.59 (d, J=4.0 Hz, 1H), 8.29(s, 1H), 7.91-7.96 (m, 1H), 7.81-7.86 (m, 1H), 7.77 (td, J=7.8, 1.6 Hz,1H), 7.61 (d, J=7.6 Hz, 1H), 7.57 (dd, J=4.0, 3.2 Hz, 1H), 7.49 (t,J=8.4 Hz, 1H), 6.86 (d, J=8.4 Hz, 2H), 6.83 (dd, J=8.4, 0.8 Hz, 1H),3.51 (s, 6H), 3.08 (s, 3H). LC-MS: m/z 520.0 (M+H)⁺

Example 53:N-(1-(2,6-dimethoxyphenyl)-2-(6-methoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)pyrimidine-2-sulfonamide

The title compound was prepared according to Method F by usingpyridine-2-sulfonamide in step D (15 mg, 29% yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 11.91 (s, 1H), 8.80 (d, J=4.8 Hz, 2H), 8.32(s, 1H), 7.91 (dd, J=7.6, 0.8 Hz, 1H), 7.83 (dd, J=8.4, 7.6 Hz, 1H),7.63 (t, J=4.8 Hz, 1H), 7.39 (t, J=8.4 Hz, 1H), 6.79-6.85 (m, 1H), 6.76(d, J=8.4 Hz, 2H), 3.50 (s, 6H), 3.06 (s, 3H). LC-MS: m/z 521.1 (M+H)⁺

Method G:

Step A: methyl 6-fluoropicolinate

Methyl iodide (20 g, 142 mmol, 3.0 equiv) was added to a suspension of6-fluoropicolinic acid (10.0 g, 71 mmol, 1.0 equiv) and silver(I)carbonate (19.5 g, 71 mmol, 1.0 equiv) in CHCl₃ (100 mL). The suspensionwas stirred at 30° C. for 1 day. Insoluble material was removed byfiltration and the filter cake was washed with CHCl₃. The filtrate wasconcentrated in vacuo to give the title compound as a light yellow solid(9.0 g, 82% yield). This material was used in the next step withoutfurther purification.

LC-MS: m/z 156.0 (M+H)⁺

Step B: 6-cyclopropoxypicolinic acid

To a mixture of cyclopropanol (1.5 g, 25.8 mmol, 3.0 equiv) in dioxane(20 mL) was added NaH (1032 mg, 25.8 mmol, 3.0 equiv) at 0° C. and themixture was stirred at 0° C. for 30 mins. Then methyl 6-fluoropicolinate(2.0 g, 12.9 mmol, 1.0 equiv) was added and the mixture was stirred at25° C. for 2 h. The reaction mixture was quenched with saturated aqueousNH₄Cl solution. The mixture was washed with EtOAc three times. Theaqueous phase was acidified with concentrated hydrochloric acid andextracted with DCM (3*30 mL). The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate and concentrated invacuo. The residue was purified by silica gel column chromatography toafford 6-cyclopropoxypicolinic acid as a white solid (600 mg, 13%yield).

LC-MS: m/z 180.0 (M+H)⁺

Step C: methyl 6-cyclopropoxypicolinate

Methyl iodide (0.41 ml, 6.59 mmol, 3.0 equiv) was added to a suspensionof 6-cyclopropoxypicolinic acid (590 mg, 3.29 mmol, 1.0 equiv) andsilver(I) carbonate (1091 mg, 3.95 mmol, 1.2 equiv) in CHCl₃ (10 ml).The suspension was stirred at 30° C. for 4 h. Insoluble material wasremoved by filtration and the filter cake was washed with CHCl₃. Thefiltrate was concentrated to give the title compound methyl6-cyclopropoxypicolinate as a light yellow oil (600 mg, 94% yield). Thismaterial was used in the next step without further purification.

LC-MS: m/z 194.0 (M+H)⁺

Step D: N-(3-bromo-5-chloropyrazin-2-yl)-6-cyclopropoxypicolinamide

To a mixture of 3-bromo-5-chloropyrazin-2-amine (644 mg, 3.1 mmol, 1.0equiv) and toluene (10 mL) was added AlMe₃ (1.6 mol/L in toluene, 4 mL,6.2 mmol, 2.0 equiv). After the mixture was stirred at 50° C. for 30mins, methyl 6-cyclopropoxypicolinate (600 mg, 3.1 mmol, 1.0 equiv) wasadded. The mixture was stirred at 110° C. for 1 h and was quenched with1N aqueous HCl solution. The mixture was extracted with DCM three times.The combined organic layers were washed with brine, dried over anhydroussodium sulfate and concentrated in vacuo. The residue was purified bysilica gel column chromatography (100% DCM) to afford the title compoundN-(3-bromo-5-chloropyrazin-2-yl)-6-cyclopropoxypicolinamide (500 mg, 44%yield).

LC-MS: m/z 369.0, 371.0 (M+H)⁺

Step E:N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-cyclopropoxypicolinamide

A suspension ofN-(3-bromo-5-chloropyrazin-2-yl)-6-cyclopropoxypicolinamide (500 mg,1.36 mmol, 1.0 equiv), 2,6-dimethoxyaniline (229 mg, 1.49 mmol, 1.1equiv), Pd(OAc)₂ (61 mg, 0.27 mmol, 0.2 equiv), Xantphos (315 mg, 0.54mmol, 0.4 equiv) and K₂CO₃ (375 mg, 2.72 mmol, 2.0 equiv) in 1,4-dioxane(3 mL) was stirred at 125° C. via microwave irradiation for 2 hoursunder N₂ atmosphere. The mixture was filtered through celite and thefiltrate was concentrated in vacuo. The residue was purified by flashchromatography (100% DCM) to afford the title compoundN-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-cyclopropoxypicolinamideas a yellow solid (247 mg, 41% yield).

LC-MS: m/z 442.1 (M+H)⁺

Step F:6-chloro-2-(6-cyclopropxypyridin-2-yl)-1-(2,6-dimethoxyphenyl)-1H-imidazo[4,5-b]pyrazine

A solution ofN-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-cyclopropoxypicolinamide(247 mg, 0.56 mmol, 1.0 equiv) in AcOH (2 mL) was stirred at 130° C. viamicrowave irradiation for 2 hours. The reaction mixture was cooled toroom temperature and the precipitate was filtered off and washed with asolvent mixture of EA/PE=1/2 to afford the title compound6-chloro-2-(6-cyclopropoxypyridin-2-yl)-1-(2,6-dimethoxyphenyl)-1H-imidazo[4,5-b]pyrazineas a light yellow solid (170 mg, 72% yield).

LC-MS: m/z 424.1 (M+H)⁺

Example 54:N-(2-(6-cyclopropoxypyridin-2-yl)-1-(2,6-dimethoxyphenyl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

A suspension of6-chloro-2-(6-cyclopropoxypyridin-2-yl)-1-(2,6-dimethoxyphenyl)-1H-imidazo[4,5-b]pyrazine(80 mg, 0.19 mmol 1.0 equiv), methanesulfonamide (36.1 mg, 0.38 mmol,2.0 equiv), CuI (72 mg, 0.38 mmol, 2.0 equiv),trans-N,N′-Dimethylcyclohexane-1,2-diamine (54 mg, 0.38 mmol, 2.0 equiv)and K₂CO₃ (78 mg, 0.57 mmol, 3.0 equiv) in DMF (3 mL) was stirred at120° C. via microwave irradiation for 2 hours under N₂ atmosphere. Themixture was diluted with EtOAc (30 mL) and filtered through celite. Thefiltrate was poured into water (50 mL). The mixture was adjusted to pH=4with 1N HCl and extracted with EA (3*100 mL). The organic layers weredried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography (eluting with DCM/MeOH=20/1) toafford the title compound as write solid (55 mg, 60% yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 11.06 (s, 1H), 8.27 (s, 1H), 7.97 (dd,J=7.6, 0.8 Hz, 1H), 7.87 (t, J=8.4 Hz, 1H), 7.40 (t, J=8.4 Hz, 1H),6.77-6.87 (m, 3H), 3.56 (s, 6H), 3.15-3.22 (m, 4H), 0.42-0.50 (m, 2H),0.27-0.41 (m, 2H). LC-MS: m/z 483.1 (M+H)⁺

Step A: 6-(2,2,2-trifluoroethoxy)picolinic acid

The mixture of methyl 6-bromopicolinate (4.3 g, 20 mmol, 1.0 equiv),ethyl 2-oxocyclohexane-1-carboxylate (680 mg, 4 mmol, 0.2 equiv), CuI(380 mg, 2 mmol, 0.1 equiv) and Cs₂CO₃ (9.1 g, 28 mmol, 1.4 equiv) in2,2,2-trifluoroethan-1-ol (14.0 g, 280 mmol, 14 equiv) was heated undernitrogen atmosphere at 78° C. for 20 hours. The reaction mixture wascooled to 20° C. and poured into water (200 mL). The mixture wasadjusted to pH=5 with 1N HCl (aq.) and extracted with DCM (3*20 mL). Thecombined organic phase was dried over anhydrous sodium sulfate andconcentrated in vacuo to afford the title compound6-(2,2,2-trifluoroethoxy)picolinic acid as yellow solid (3.3 g, 74%yield).

LC-MS: m/z 222.0 (M+H)⁺

Step B: methyl 6-(2,2,2-trifluoroethoxy)picolinate

To a solution of 6-(2,2,2-trifluoroethoxy)picolinic acid (2.2 g, 10mmol, 1.0 equiv) in methanol (20 mL) were added 2 drops of H₂SO₄ (con.).The mixture was stirred at 20° C. for 20 hours, diluted with H₂O (100mL) and extracted with DCM (3*20 mL). The combined organic phase wasdried over anhydrous sodium sulfite and concentrated in vacuo. Theresidue was purified by silica gel chromatography (PE/EA=20/1) to affordthe title compound methyl 6-(2,2,2-trifluoroethoxy)picolinate as acolorless oil (2.1 g, 88% yield).

LC-MS: m/z 236.1 (M+H)⁺

Example 55:N-(1-(2,6-dimethoxyphenyl)-2-(6-(trifluoroethoxy)pyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

The title compound was prepared according to Method G by using methyl6-(2,2,2-trifluoroethoxy)picolinate in step D. (15 mg, 10% yield).

¹H NMR (400 MHz, CDCl₃) δ: 8.55 (s, 1H), 8.27 (d, J=4.0 Hz, 1H), 7.79(t, J=8.8 Hz, 1H), 7.43 (t, J=8.4 Hz, 1H), 7.07 (s, 1H), 6.86 (d, J=4.0Hz, 1H), 6.73 (d, J=4.4 Hz, 2H), 3.74 (q, J=8.8 Hz, 2H), 3.63 (s, 6H),3.18 (s, 3H). LC-MS: m/z 525.1 (M+H)⁺

Step A: methyl 6-(trifluoromethoxy)picolinate

To a solution of 2-chloro-6-(trifluoromethoxy)pyridine (5.0 g, 25.3mmol, 1.0 equiv) in MeOH (120 mL) was added Pd(dppf)Cl₂ (930 mg, 1.27mmol, 0.05 equiv). The mixture was stirred at 100° C. under hydrogenatmosphere (50 Psi) for 48 hours. The reaction mixture was cooled to 20°C. and concentrated in vacuo. The residue was purified by silica gelchromatography (PE/EA=10/1) to afford the title compound methyl6-(trifluoromethoxy)picolinate as yellow oil (3.85 g, 68% yield).

LC-MS: m/z 222.0 (M+H)⁺

Example 56:N-(1-(2,6-dimethoxyphenyl)-2-(6-(trifluoromethoxy)pyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

The title compound was prepared according to Method G by using methyl6-(trifluoromethoxy)picolinate in step D (30 mg, 15% yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.26 (t, J=4.0 Hz, 1H), 8.19 (s, 1H), 8.17(t, J=7.6 Hz, 1H), 7.43 (t, J=8.8 Hz, 1H), 7.29 (d, J=4.0 Hz, 1H), 6.79(d, J=4.4 Hz, 2H), 3.54 (s, 6H), 3.10 (s, 3H). LC-MS: m/z 511.1 (M+H)⁺

Example 57:N-(1-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-1H-imidazo[4,5-b]pyrazin-6-yl)benzenesulfonamide

The title compound was prepared according to Method G by using ethyl2-ethoxyacetate in step D and benzenesulfonamide in step G (39 mg, 29%yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 11.52 (s, 1H), 8.16 (s, 1H), 7.69 (d, J=7.6Hz, 2H), 7.54-7.70 (m, 2H), 7.36 (t, J=7.6 Hz, 2H), 6.94 (d, J=8.4 Hz,2H), 4.42 (s, 2H), 3.65 (s, 6H), 3.28 (q, J=7.2 Hz, 2H), 0.92 (t, J=7.2Hz, 3H). LC-MS: m/z 470.1 (M+H)⁺

Method H:

Step A: 6-bromo-N²-(pentan-3-yl)pyrazine-2,3-diamine

A suspension of 3,5-dibromopyrazin-2-amine (1.0 g, 3.98 mmol, 1.0 equiv)in pentan-3-amine (10 mL) was stirred at 150° C. via microwaveirradiation for 1 hour. The mixture was diluted with water (15 mL) andextracted with EtOAc (3*50 mL). The combined organic layers were driedover anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography (eluting with PE/EtOAc=20/1 to5/1) to afford the title compound6-bromo-N²-(pentan-3-yl)pyrazine-2,3-diamine as light yellow solid (0.9g, 88% yield). LC-MS: m/z 259.1, 261.1 (M+H)⁺

Step B:N-(5-bromo-3-(pentan-3-ylamino)pyrazin-2-yl)-6-ethoxypicolinamide

To a solution of 6-bromo-N²-(pentan-3-yl)pyrazine-2,3-diamine (900 mg,3.5 mmol, 1.1 equiv) in toluene (20 mL) was added Al(Me)₃ (1.6 mol/L intoluene, 10 mL, 15.9 mmol, 5 equiv) dropwise at room temperature. Afterthe mixture was stirred at 50° C. for 30 mins, ethyl 6-ethoxypicolinate(686 mg, 3.2 mmol, 1.0 equiv) was added and the mixture was stirred at110° C. for 2 hours. The reaction mixture was quenched with water (50mL), followed by extraction with EtOAc (3*50 mL). The combined organiclayers were washed with brine (50 mL), dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash columnchromatography (eluting with PE/EtOAc=20/1 to 5/1) to afford the titlecompoundN-(5-bromo-3-(pentan-3-ylamino)pyrazin-2-yl)-6-ethoxypicolinamide aslight yellow solid (0.65 g, 46% yield). LC-MS: m/z 408.1, 410.1 (M+H)⁺

Step C:6-bromo-2-(6-ethoxypyridin-2-yl)-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyrazine

To a solution ofN-(5-bromo-3-(pentan-3-ylamino)pyrazin-2-yl)-6-ethoxypicolinamide (650mg, 1.6 mmol, 1.0 equiv) in AcOH (10 mL) was added 1 drop of POCl₃. Themixture was stirred at 120° C. via microwave irradiation for 2 hours.The mixture was cooled to room temperature, evaporated and the residuewas purified by flash column chromatography (eluting with PE/EtOAc=20/1to 5/1) to afford the title compound6-bromo-2-(6-ethoxypyridin-2-yl)-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyrazineas a light yellow solid (450 mg, 72% yield).

LC-MS: m/z 390.1, 392.1 (M+H)⁺

Example 58:N-(2-(6-ethoxypyridin-2-yl)-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

A suspension of6-bromo-2-(6-ethoxypyridin-2-yl)-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyrazine(50 mg, 0.13 mmol, 1.0 equiv), methanesulfonamide (24 mg, 0.26 mmol, 3.0equiv), CuI (49 mg, 0.26 mmol, 3.0 equiv),trans-N,N′-Dimethylcyclohexane-1,2-diamine (37 mg, 0.26 mmol, 3.0 equiv)and K₂CO₃ (53 mg, 0.39 mmol, 3 equiv) in DMF (5 mL) was stirred at 115°C. via microwave irradiation for 1.5 h under N₂ atmosphere. The mixturewas diluted with water (15 mL) and extracted with EtOAc (3*50 mL). Thecombined organic layers were dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by prep-TLC(PE/EtOAc=1/2) to afford the title compoundN-(2-(6-ethoxypyridin-2-yl)-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamideas a light yellow solid (40 mg, 76% yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 11.18 (s, 1H), 8.19 (s, 1H), 7.94 (t, J=7.6Hz, 1H), 7.89 (dd, J=7.6 Hz, 0.8 Hz, 1H), 7.01 (dd, J=8.4 Hz, 0.8 Hz,1H), 5.74-5.79 (m, 1H), 4.40 (q, J=7.2 Hz, 2H), 3.42 (s, 3H), 2.34-2.42(m, 2H), 2.01-1.99 (m, 2H), 1.39 (t, J=7.2 Hz, 3H), 0.70 (t, J=7.6 Hz,6H). LC-MS: m/z 405.2 (M+H)⁺

Example 59:N-(2-(6-ethoxypyridin-2-yl)-1-isopropyl-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

The title compound was prepared according to Method H by usingpropan-2-amine in step A.

¹HNMR (400 MHz, DMSO-d₆) δ: 11.17 (s, 1H), 8.18 (s, 1H), 7.95 (t, J=7.6Hz, 1H), 7.85 (dd, J=7.6 Hz, 0.8 Hz, 1H), 7.0 (dd, J=8.4 Hz, 0.8 Hz,1H), 5.93-6.0 (m, 1H), 4.41 (q, J=7.2 Hz, 2H), 3.45 (s, 3H), 1.73 (d,J=6.8 Hz, 6H), 1.38 (t, J=7.2 Hz, 3H). LC-MS: m/z 377.1 (M+H)⁺

Step A: 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate

To a solution of 3-methylbutane-1,3-diol (20.8 g, 200 mmol, 1.0 equiv)in Pyridine (40 mL) was added TsCl (39.6 g, 20 mmol, 1.0 equiv) at 0° C.The reaction mixture was stirred at room temperature for 16 hours. Thereaction mixture was neutralized with saturated NH₄Cl and extracted withDCM (3*100 mL). The extract was concentrate in vacuo and the residue waspurified by flash chromatography (PE/EA=1/1) to afford the titlecompound 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate as a yellow(45 g 90% yield).

LC-MS: m/z 259.0 (M+H)⁺

Step B: 4-iodo-2-methylbutan-2-ol

To a solution of 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (6 g,23.2 mmol, 1.0 equiv) in acetone (100 mL) was added NaI (8.7 g, 58 mmol,2.5 equiv). The reaction mixture was stirred at 60° C. for 2 hours andconcentrated in vacuo. The residue was diluted with EtOAc, washed withwater and brine. The organic phase was concentrated in vacuo to affordthe title crude compound 4-iodo-2-methylbutan-2-ol as a brown oil (3.6g, 72% yield).

LC-MS: m/z 215.0 (M+H)⁺

Step C: 4-(benzo[d]thiazol-2-ylthio)-2-methylbutan-2-ol

To a solution of 4-iodo-2-methylbutan-2-ol (3.6 g, 11.8 mmol, 1.0 equiv)and benzo[d]thiazole-2-thiol (3.4 g, 20.2 mmol, 1.2 equiv) in THF (85mL) was added Et₃N (3.4 g, 33.6 mmol, 2.0 equiv). The resulting mixturewas stirred at 85° C. for 16 hours. The reaction solution wasconcentrated in vacuo and the residue was purified by flashchromatography (PE/EA=10/1) to afford the title compound4-(benzo[d]thiazol-2-ylthio)-2-methylbutan-2-ol as a yellow solid (3.5g, 83% yield).

LC-MS: m/z 254.0 (M+H)⁺

Step D: 4-(benzo[d]thiazol-2-ylsulfonyl)-2-methylbutan-2-ol

To a suspension of 4-(benzo[d]thiazol-2-ylthio)-2-methylbutan-2-ol (3.3g, 13 mmol, 1.0 equiv) in DCM (80 mL) was added m-CPBA (5.8 g, 28.7mmol, 2.2 equiv). The resulting mixture was stirred at room temperaturefor 16 hours. The reaction mixture was washed with Na₂SO₃ (aq.),saturated NaHCO₃ (aq.) and brine successively, dried over Na₂SO₄,concentrated in vacuo and the residue was purified by flash columnchromatography (PE/EtOAc=2/1) to afford the title compound4-(benzo[d]thiazol-2-ylsulfonyl)-2-methylbutan-2-ol as a white solid(3.5 g, 88% yield).

LC-MS: m/z 286.0 (M+H)⁺

Step E:24(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)butyl)sulfonyl)benzo[d]thiazole

To a solution of 4-(benzo[d]thiazol-2-ylsulfonyl)-2-methylbutan-2-ol(0.5 g, 1.75 mmol, 1.0 equiv) in DCM (15 mL) were added DHP (0.2 g, 2.28mmol, 1.3 equiv) and PPTS (50 mg) at 0° C. The mixture was stirred atroom temperature for 2 hours. The mixture was concentrated and theresidue was purified by flash chromatography (PE/EtOAc=7/1) to affordthe title compound2-((3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)butyl)sulfonyl)benzo[d]thiazoleas a white solid (0.6 g, 94% yield).

LC-MS: m/z 370.1 (M+H)⁺

Step F: 3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)butane-1-sulfonamide

To a suspension of2-((3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)butyl)sulfonyl)benzo[d]thiazole(550 mg, 1.5 mmol, 1.0 equiv) in MeOH (15 mL) was added K₂CO₃ (1.0 g,7.5 mmol, 5.0 equiv). After the mixture was stirred at 25° C. for 2hours, NH₂OSO₃H (250 mg, 2.3 mmol, 1.5 equiv) was added. The mixture wasthen stirred at room temperature for 16 hours. The mixture was filteredand the filtrate was concentrated in vacuo. The residue was purified byflash chromatography (PE/EtOAc=1/1) to afford the title compound3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)butane-1-sulfonamide as acolorless oil (210 mg, 59% yield).

LC-MS: m/z 252.1 (M+H)⁺

Step G:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)butane-1-sulfonamide

A suspension of6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(100 mg, 0.22 mmol, 1.0 equiv),3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)butane-1-sulfonamide (100 mg,0.22 mmol, 2.0 equiv), (1R,2R)—N¹,N²-dimethylcyclohexane-1,2-diamine (62mg, 0.44 mmol, 3.0 equiv), CuI (84 mg, 0.44 mmol, 3.0 equiv) and K₂CO₃(91 mg, 0.66 mmol, 3 equiv) in DMF (4 mL) was stirred at 115° C. viamicrowave irradiation for 2 hours under N₂ atmosphere. The reaction waspoured into H₂O (20 mL) and extracted with ethyl acetate. The extractwas washed with water and brine, dried over anhydrous MgSO₄ andconcentrated in vacuo. The residue was purified by flash columnchromatography (PE/EtOAc=1/1) to afford the title compoundN-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)butane-1-sulfonamideas a yellow oil (100 mg, 73% yield).

LC-MS: m/z 627.3 (M+H)⁺

Example 60:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-3-hydroxy-3-methylbutane-1-sulfonamide

To a suspension ofN-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)butane-1-sulfonamide(100 mg, 0.16 mmol, 1.0 equiv) in MeOH (4 mL) was added HCl (con. 0.3mL) and the resulting mixture was stirred at room temperature for 10mins. The mixture was evaporated and diluted with EtOAc, then washedwith NaHCO₃ (aq.). The organic phase was concentrated in vacuo and theresidue was purified by Prep-TLC (DCM/MeOH=20/1) to afford the titlecompoundN-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-3-hydroxy-3-methylbutane-1-sulfonamideas a yellow solid (35 mg, 40% yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.27 (s, 1H), 7.94 (dd, J=7.6 Hz, 1H), 7.84(t, J=8.0 Hz, 1H), 7.42 (t, J=8.4 Hz, 1H), 6.86-6.80 (m, 3H), 4.36 (s,1H), 3.56 (s, 6H) 3.36 (q, J=7.2 Hz, 2H), 3.30-3.28 (m, 2H), 1.68-1.64(m, 2H), 3.52 (s, 6H), 1.03 (t, J=7.2 Hz, 3H), 0.91 (s, 6H). LC-MS: m/z543.2 (M+H)⁺

Step A: methyl 1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropanecarboxylate

Methyl 1-hydroxycyclopropanecarboxylate (5 g, 43.1 mmol, 1.0 equiv) wasdissolved in DCM (40 mL). Then DHP (3.8 g, 45.2 mmol, 1.05 equiv) andPPTS (1.1 g, 4.3 mmol, 0.1 equiv) were added. The mixture was stirred atroom temperature for 3 hours. After that, DCM was removed and to theresidue were added Et₂O and brine. The organic layer was separated,dried over anhydrous Na₂SO₄, concentrated and purified by columnchromatography (PE/EtOAc=20/1) to afford the title compound methyl1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropanecarboxylate as colorlessoil (7.66 g, 93% yield).

LC-MS: m/z 201.1 (M+H)⁺

Step B: (1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)methanol

The solution of methyl1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropanecarboxylate (7.66 g, 38.3mmol, 1.0 equiv) in THF (30 mL) was cooled to 0° C. Then LiAlH₄ (1 mol/Lin THF, 76.6 mL, 76.6 mmol, 3.0 equiv) was added dropwise. After stirredat 0° C. for 0.5 h, the reaction mixture was diluted with Et₂O andquenched by adding H₂O (3 mL) dropwise. After that, 4 N NaOH (aq. 3 mL)was added followed by addition of H₂O (3*3 mL). The resulting suspensionwas filtered and the filter cake was washed with EtOAc three times. Theorganic layer of the filtrate was separated, washed with brine, driedover Na₂SO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography (PE/EtOAc=3/1) to afford the title compound(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)methanol as colorless oil(5.8 g, 88% yield).

LC-MS: m/z 172.2 (M+H)⁺

Step C:2-(((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)methyl)thio)benzo[d]thiazole

(1-((Tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)methanol (2 g, 11.6 mmol,1.0 equiv), benzo[d]thiazole-2-thiol (2.24 g, 14.5 mmol, 1.25 equiv) andPPh₃ (3.8 g, 14.5 mmol, 1.25 equiv) were dissolved in anhydrous THF (12mL). The solution was cooled to −78° C. and DIAD (2.93 g, 14.5 mmol,1.25 equiv) was added dropwise. The mixture was stirred at roomtemperature overnight. After that, the mixture was filtered and thefiltrate was concentrated in vacuo. The residue was purified by columnchromatography to afford the title compound2-(((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)methyl)thio)benzo[d]thiazoleas light yellow solid (3.03 g, 81% yield).

LC-MS: m/z 322.1 (M+H)⁺

Step D: 1-((benzo[d]thiazol-2-ylsulfonyl)methyl)cyclopropanol

2-(((1-((Tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)methyl)thio)benzo[d]thiazole(3.03 g, 9.4 mmol, 1.0 equiv) was dissolved in DCM (10 mL) and m-CPBA(3.57 g, 20.7 mmol, 2.2 equiv) was added. The solution was stirred atroom temperature overnight. The reaction mixture was washed with Na₂SO₃(aq.), saturated NaHCO₃ (aq.) and brine successively, dried over Na₂SO₄,concentrated in vacuo and the residue was purified by columnchromatography to afford the title compound1-((benzo[d]thiazol-2-ylsulfonyl)methyl)cyclopropanol as colorless oil(1.4 g, 55% yield)

LC-MS: m/z 270.0 (M+H)⁺

Step E:2-(((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)methyl)sulfonyl)benzo[d]thiazole

1-((Benzo[d]thiazol-2-ylsulfonyl)methyl)cyclopropanol (1.4 g, 5.20 mmol,1.0 equiv) was dissolved in DCM (2 mL). Then DHP (492 mg, 5.72 mmol, 1.1equiv) and PPTS (261 mg, 1.04 mmol, 0.2 equiv) were added. The mixturewas stirred at room temperature overnight. Then DCM was removed and tothe residue were added Et₂O and brine. The organic layer was separated,dried over Na₂SO₄, concentrated and purified with column chromatography(PE/EtOAc=10/1) to give2-(((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)methyl)sulfonyl)benzo[d]thiazoleas white solid (839 mg, 45% yield).

LC-MS: m/z 354.1 (M+H)⁺

Step F: (1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)methanesulfonamide

2-(((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)methyl)sulfonyl)benzo[d]thiazole(839 mg, 2.37 mmol, 1.0 equiv) was dissolved in MeOH (4 mL) and K₂CO₃(492 mg, 3.56 mmol, 1.5 equiv) was added. The mixture was stirred atroom temperature for 1.5 h. After which time, another batch K₂CO₃ (982mg, 7.11 mmol, 3 equiv) and NH₂OSO₃ (401 mg, 3.56 mmol, 1.5 equiv) wereadded. The reaction mixture was stirred at room temperature overnight.Then MeOH was removed and the residue was dissolved in H₂O. The mixturewas extracted with EtOAc three times. The organic layers were combined,washed with brine, dried over Na₂SO₄, concentrated and purified viacolumn chromatography (PE/EtOAc=2/1) to give(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)methanesulfonamide ascolorless oil (210 mg, 38% yield).

¹H NMR (400 MHz, CDCl₃) δ: 4.95 (s, 2H), 4.56 (dd, J=8.0 Hz, J=2.4 Hz,1H), 3.97 (dd, J=14.8 Hz, J=1.6 Hz, 1H), 3.90-3.94 (m, 1H), 3.40-3.48(m, 1H), 2.84 (d, J=14.8 Hz, 1H), 1.74-1.78 (m, 2H), 1.34-1.59 (m, 4H),1.09-1.05 (m, 1H), 0.90-0.95 (m, 2H), 0.60-0.67 (m, 1H).

Step G:N-(1-(2,6-dimethoxyphenyl-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropylmethanesulfonamide

A suspension of6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(69 mg, 0.15 mmol, 0.5 equiv),(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)methanesulfonamide (71 mg,0.30 mmol, 1.0 equiv), CuI (57 mg, 0.30 mmol, 1.0 equiv),trans-N,N′-Dimethylcyclohexane-1,2-diamine (43 mg, 0.30 mmol, 1.0 equiv)and K₂CO₃ (68 mg, 0.45 mmol, 1.5 equiv) in DMF (1 mL) was stirred at115° C. via microwave irradiation for 2 hours under N₂ atmosphere. Themixture was diluted with water (5 mL), extracted with EtOAc three times.The combined organic layers were washed with brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by columnchromatography (PE/EtOAc=4/1) to giveN-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)methanesulfonamideas a yellow solid (40 mg, 44% yield).

LC-MS: m/z 611.2 (M+H)⁺

Example 61:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(1-hydroxycyclopropyl)methanesulfonamide

N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)methanesulfonamide(45 mg, 0.074 mmol, 1.0 equiv) was dissolved in DCM (1 mL) and PPTS (19mg, 0.037 mmol, 0.5 equiv) was added. The mixture was stirred at roomtemperature overnight. The mixture was concentrated and purified byreverse phase flash chromatography to give the title compound as whitesolid (30 mg, 77% yield).

¹H NMR (400 MHz, DMSO-d₆) δ:11.06 (br, 1H), 8.25 (s, 1H), 7.91 (d, J=7.2Hz, 1H), 7.83 (t, J=8.0 Hz, 1H), 7.41 (t, J=8.4 Hz, 1H), 6.83 (d, J=8.4Hz, 2H), 6.78 (d, J=7.6 Hz, 1H), 5.38 (br. s, 1H), 3.57 (s, 6H), 3.49(s, 2H), 3.35 (q, J=7.2 Hz, 2H), 1.00 (t, J=7.2 Hz, 3H), 0.57-0.60 (m,2H), 0.41-0.44 (m, 2H). LC-MS: m/z 527.3 (M+H)⁺

N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)-1-(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)methanesulfonamide

The title compound was prepared according to Method C, step D, startingfrom5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(Example 15) by using(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)methanesulfonamide (121mg, 66% yield).

LC-MS: m/z 611.0 (M+H)⁺

Example 62:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)-1-(1-hydroxycyclopropyl)methanesulfonamide

The title compound was prepared following the same approach of thepreparation of Example 61 (22 mg, 28% yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 7.94-8.02 (m, 2H), 7.81-7.92 (m, 1H), 7.46(t, J=8.4 Hz, 1H), 6.82-6.89 (m, 3H), 3.81 (s, 2H), 3.58 (s, 6H), 3.39(q, J=7.2 Hz, 2H), 1.03 (t, J=7.2 Hz, 3H), 0.71 (d, J=7.6 Hz, 4H).LC-MS: m/z 527.3 (M+H)⁺

Step A: N-(2-bromo-6-chloropyridin-3-yl)-6-ethoxypicolinamide

To a solution of 2-bromo-6-chloropyridin-3-amine (2 g, 10 mmol, 1.0equiv) in toluene (30 mL) was added trimethylaluminum (2 mol/L intoluene, 7.5 mL, 15 mmol, 1.5 equiv) at 0° C. After the mixture wasstirred at 80° C. for 1 hour, ethyl 6-ethoxypicolinate (2 g, 10 mmol,1.0 equiv) was added. The resulting mixture was stirred at 90° C. for 16hours. The mixture was quenched with 4N HCl (aq.) and extracted with DCM(3*80 mL). The extract was washed with brine (100 mL), dried overanhydrous Na₂SO₄ and concentrated in vacuo.

The residue was washed with MeOH to afford the title compoundN-(2-bromo-6-chloropyridin-3-yl)-6-ethoxypicolinamide as a yellow solid(2.3 g, 67% yield).

LC-MS: m/z 355.0, 357.0 (M+H)⁺

Step B:N-(6-chloro-2-((2,6-dimethoxyphenyl)amino)pyridin-3-yl)-6-ethoxypicolinamide

A suspension of N-(2-bromo-6-chloropyridin-3-yl)-6-ethoxypicolinamide(1.2 g, 3.4 mmol, 1.0 equiv), 2,6-dimethoxyaniline (516 mg, 3.4 mmol,1.0 equiv), Pd₂(dba)₃ (616 mg, 0.7 mmol, 0.2 equiv), Xantphos (578 mg,1.4 mmol, 0.4 equiv) and K₂CO₃ (1.4 g, 10 mmol, 3 equiv) in 1,4-dioxane(15 mL) was stirred at 100° C. via microwave irradiation for 2 hoursunder N₂ atmosphere. The mixture was diluted with DCM (20 mL) andfiltered through celite. The filtrate was concentrated in vacuo and theresidue was purified by flash column chromatography (PE/EtOAc=5/1) toafford the title compoundN-(6-chloro-2-((2,6-dimethoxyphenyl)amino)pyridin-3-yl)-6-ethoxypicolinamideas a white solid (1 g, 69% yield).

LC-MS: m/z 429.1 (M+H)⁺

Step C:5-chloro-3-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-3H-imidazo[4,5-b]pyridine

To a solution ofN-(6-chloro-2-((2,6-dimethoxyphenyl)amino)pyridin-3-yl)-6-ethoxypicolinamide(0.3 g, 0.7 mmol, 1.0 equiv) in AcOH (10 mL) was added 1 drop of POCl₃(cat.). The mixture was stirred at 120° C. via microwave irradiation for2 hours and then cooled to room temperature. The precipitate wasfiltered off and washed with a mixture of EtOAc/PE=1/2 to afford thetitle compound5-chloro-3-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-3H-imidazo[4,5-b]pyridineas a white solid (60 mg, 20% yield).

LC-MS: m/z 411 (M+H)⁺

Example 63:N-(3-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl)methanesulfonamide

A suspension of5-chloro-3-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-3H-imidazo[4,5-b]pyridine(70 mg, 0.17 mmol, 1.0 equiv), methanesulfonamide (32 mg, 0.34 mmol, 3.0equiv), CuI (65 mg, 0.34 mmol, 3.0 equiv),trans-N,N′-Dimethylcyclohexane-1,2-diamine (48 mg, 0.34 mmol, 3.0 equiv)and K₂CO₃ (70 mg, 0.51 mmol, 3 equiv) in DMF (3 mL) was stirred at 120°C. via microwave irradiation for 10 hours under N₂ atmosphere. Themixture was diluted with EtOAc (100 mL) and filtered through celite. Thefiltrate was poured into water (150 mL), followed by extraction withEtOAc (2*100 mL). The combined organic layers were dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by flashcolumn chromatography (eluting with DCM/MeOH=20/1) to afford the titlecompoundN-(3-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl)methanesulfonamideas a white solid (30 mg, 30% yield).

¹HNMR (400 MHz, DMSO-d₆) δ: 10.58 (s, 1H), 8.10 (d, J=8.4 Hz, 1H), 7.86(d, J=6.8 Hz, 1H), 7.79 (t, J=7.6 Hz, 1H), 7.41 (t, J=8.4 Hz, 1H), 6.94(d, J=8.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 2H), 6.74 (d, J=7.6 Hz, 1H), 3.55(s, 6H), 3.39 (q, J=7.2 Hz, 2H), 3.31 (s, 3H), 1.02 (t, J=7.2 Hz, 3H).LC-MS: m/z 470.1 (M+H)⁺

Step A: N-3,5-dibromo-6-chloropyrazin-2-yl)-6-ethoxypicolinamide

To a solution of 3,5-dibromo-6-chloropyrazin-2-amine (2 g, 6.97 mmol,1.0 equiv) in toluene (50 mL) was added Al(Me)₃ (2 mol/L in toluene, 5.2mL, 10.4 mmol, 1.5 equiv) dropwise at 0° C. under N₂ atmosphere. Afterthe mixture was stirred at 0° C. for 30 mins and at 50° C. for 30 mins,ethyl 6-ethoxypicolinate (1.36 g, 6.97 mmol, 1.0 equiv) was added. Themixture was stirred at 50° C. for 3 hours. The reaction mixture wasquenched with 1N HCl (100 mL), followed by extraction with DCM (2*50mL). The combined organic layers were dried over anhydrous Na₂SO₄ andconcentrated in vacuo. MeOH (50 mL) was added into the residue. Theprecipitate was filtered off to afford the title compoundN-(3,5-dibromo-6-chloropyrazin-2-yl)-6-ethoxypicolinamide as a yellowsolid (2.3 g, 76% yield).

LC-MS: m/z 434.9, 436.9, 438.9 (M+H)⁺

Step B:N-(5-bromo-6-chloro-3-((2,6-dimethoxyphenylamino)pyrazin-2-yl)-6-ethoxypicolinamide

A suspension ofN-(3,5-dibromo-6-chloropyrazin-2-yl)-6-ethoxypicolinamide (1.0 g, 2.3mmol, 1.0 equiv), 2,6-dimethoxyaniline (351 mg, 2.3 mmol, 1.0 equiv),Pd₂(dba)₃ (420 mg, 0.46 mmol, 0.2 equiv), Xantphos (530 mg, 0.52 mmol,0.4 equiv) and K₂CO₃ (632 mg, 4.6 mmol, 3.0 equiv) in 1,4-dioxane (15mL) was stirred at 100° C. via microwave irradiation for 2 hours underN₂ atmosphere. The mixture was filtered and the filtrate wasconcentrated to dryness. The residue was purified by silica gel columnchromatography (eluting with PE/EtOAc=10/1 to 5/1)) to afford the titlecompoundN-(5-bromo-6-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamideas a yellow solid (480 mg, 41% yield). LC-MS: m/z 508.0, 510.0 (M+H)⁺

Step C:6-bromo-5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine

The solution ofN-(5-bromo-6-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamideamide (400 mg, 0.78 mmol, 1.0 equiv) in AcOH (10 mL) was stirred at 110°C. via microwave irradiation for 4 hours. The mixture was cooled to roomtemperature and the precipitate was filtered off to afford the titlecompound6-bromo-5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineas a yellow solid (220 mg, 57% yield).

LC-MS: m/z 490.0, 492.0 (M+H)⁺

Example 64:N-(5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

A suspension of6-bromo-5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(200 mg, 0.41 mmol, 1.0 equiv), methanesulfonamide (38 mg, 0.41 mmol,1.0 equiv), CuI (155 mg, 0.82 mmol, 3.0 equiv),trans-N,N′-Dimethylcyclohexane-1,2-diamine (116 mg, 0.82 mmol, 3.0equiv) and K₂CO₃ (168 mg, 1.2 mmol, 3 equiv) in DMF (10 mL) was stirredat 60° C. via microwave irradiation for 1 hour under N₂ atmosphere. Themixture was diluted with 1N HCl (20 mL) and extracted with EtOAc (2*50mL). The combined organic layers were dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash columnchromatography to afford the title compound as a yellow solid (120 mg,59% yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 10.69 (br. s, 1H), 7.94 (d, J=7.2 Hz, 1H),7.87 (t, J=8.0 Hz, 1H), 7.46 (t, J=8.4 Hz, 1H), 6.83-6.87 (m, 3H), 3.57(s, 6H), 3.39 (q, J=7.2 Hz, 2H), 3.12 (s, 3H), 1.02 (t, J=7.2 Hz, 3H).LC-MS: m/z 505.0 (M+H)⁺

Step A: 2-amino-6-allylpyrazine

A suspension of 6-bromopyrazin-2-amine (1.0 g, 5.7 mmol, 1.0 equiv),2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.9 g, 11.5 mmol, 3.0equiv), Pd(dppf)Cl₂.CH₂Cl₂ (470 mg, 0.57 mmol, 0.1 equiv) and K₂CO₃(2.37 g, 1.72 mmol, 0.06 equiv) in THF/H₂O (15 mL/1.5 mL) was stirred at100° C. under N₂ atmosphere overnight. The reaction mixture was pouredonto H₂O (20 mL) and extracted with EtOAc (3*20 mL). The extracts werewashed with water (10 mL) and brine (10 mL), dried over MgSO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (eluting with PE/EtOAc=6/1 to 2/1)) to afford the titlecompound 2-amino-6-allylpyrazine as a yellow solid (570 mg, 74% yield).LC-MS: m/z 136.2 (M+H)⁺

Step B: 2-(bis(tert-butoxycarbonylamino)-6-allylpyrazine

To a solution of 2-amino-6-allylpyrazine (1 g, 7.4 mmol, 1.0 equiv) inTHF (30 mL) was added DMAP (181 mg, 1.48 mmol, 0.2 equiv) and Boc₂O (6.5g, 29.6 mmol, 4.0 equiv) at 0° C. The resulting mixture was stirred atroom temperature for 3 hours. The reaction solution was concentrated invacuo and the residue was purified by silica gel column chromatography(eluting with PE/EtOAc=40/1) to afford the title compound2-(bis(tert-butoxycarbonyl)amino)-6-allylpyrazine as a white solid (1.6g, 64% yield). LC-MS: m/z 336.4 (M+H)⁺

Step C: 2-amino-6-(cyclopropylmethyl)pyrazine

To a solution of Et₂Zn (9 mL, 17.9 mmol, 10.0 equiv) in DCM (100 mL) wasadded CH₂I₂ (4.8 g, 17.9 mmol, 10.0 equiv) at 0° C. under N₂ pressure.After the resulting mixture was stirred at 0° C. under N₂ pressure for20 mins, 2-(bis(tert-butoxycarbonyl)amino)-6-allylpyrazine (600 mg, 1.79mmol, 1.0 equiv) was added. The mixture was stirred at room temperaturefor 1 hour under N₂ pressure. The reaction mixture was poured ontoaqueous NH₄Cl (50 mL) and extracted with EtOAc (2*50 mL). The extractswere dried over anhydrous MgSO₄ and concentrated in vacuo. The residuewas purified by flash column chromatography (PE/EtOAc=10/1 to 2/1) toafford the title compound 2-amino-6-(cyclopropylmethyl)pyrazine as awhite solid (120 mg, 23% yield).

LC-MS: m/z 150.2 (M+H)⁺

Step D: 2-amino-3,5-dibromo-6-(cyclopropylmethyl)pyrazine

To a solution of 2-amino-6-(cyclopropylmethyl)pyrazine (230 mg, 1.5mmol, 1.0 equiv) in THF (10 mL) was added NBS (1.1 g, 6.17 mmol, 4.0equiv) at 0° C. under N₂ pressure. The mixture was stirred at roomtemperature for 3 hours. The mixture was concentrated in vacuo and theresidue which was purified by silica gel column chromatography (elutingwith PE/EtOAc=40/1 to 20/1)) to afford the title2-amino-3,5-dibromo-6-(cyclopropylmethyl)pyrazine as yellow oil (240 mg,49% yield).

LC-MS: m/z 305.9, 307.9, 309.9 (M+H)⁺

Step E:N-(3,5-dibromo-6-(cyclopropylmethyl)pyrazin-2-yl)-6-ethoxypicolinamide

To a solution of 3,5-dibromo-6-(cyclopropylmethyl)pyrazin-2-amine (240mg, 0.78 mmol, 1.0 equiv) in toluene (5 mL) was added Al(Me)₃ (2 mol/Lin toluene, 0.6 mL, 1.17 mmol, 1.5 equiv) dropwise at 0° C. under N₂atmosphere. After the mixture was stirred at 0° C. for 20 mins and at50° C. for 30 mins, ethyl 6-ethoxypicolinate (230 mg, 1.17 mmol, 1.5equiv) was added. The resulting mixture was stirred at 50° C. for 4hours. The reaction mixture was quenched with 1N HCl (10 mL), followedby extraction with DCM (2*30 mL). The combined organic layers were driedover anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (eluting withPE/EtOAc=20/1)) to afford the title compoundN-(3,5-dibromo-6-(cyclopropylmethyl)pyrazin-2-yl)-6-ethoxypicolinamideas a white solid (320 mg, 89% yield).

LC-MS: m/z 455.0, 457.0, 459.0 (M+H)⁺

Step F:N-(5-bromo-6-(cyclopropylmethyl)-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide

A suspension ofN-(3,5-dibromo-6-(cyclopropylmethyl)pyrazin-2-yl)-6-ethoxypicolinamide(120 mg, 0.26 mmol, 1.0 equiv), 2,6-dimethoxyaniline (40 mg, 0.26 mmol,1.0 equiv), Pd₂(dba)₃ (48 mg, 0.053 mmol, 0.2 equiv), Xantphos (61 mg,0.11 mmol, 0.4 equiv) and K₂CO₃ (73 mg, 0.53 mmol, 3.0 equiv) in1,4-dioxane (4 mL) was stirred at 100° C. via microwave irradiation for2 hours under N₂ atmosphere. The mixture was filtered and the filtratewas concentrated to dryness. The residue was purified by Prep-TLC(PE/EtOAc=15/1) to afford the title compoundN-(5-bromo-6-(cyclopropylmethyl)-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamideas yellow oil (55 mg, 40% yield)

LC-MS: m/z 528.1, 530.1 (M+H)⁺

Step G:6-bromo-5-(cyclopropylmethyl)-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine

The solution ofN-(5-bromo-6-(cyclopropylmethyl)-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide(100 mg, 0.19 mmol, 1.0 equiv) in AcOH (5 mL) was stirred at 110° C. viamicrowave irradiation for 3 hours. The mixture was concentrated invacuo. The residue was dissolved in EtOAc (40 mL) and washed with NaHCO₃(aq., 30 mL). The organic phase was dried over anhydrous MgSO₄ andconcentrated in vacuo. The residue was purified by Prep-TLC (100% DCM)to afford the title compound6-bromo-5-(cyclopropylmethyl)-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineas a white solid (80 mg, 83% yield).

LC-MS: m/z 510.1, 512.1 (M+H)⁺

Example 65:N-(5-(cyclopropylmethyl)-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

A suspension of6-bromo-5-(cyclopropylmethyl)-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(80 mg, 0.16 mmol, 1.0 equiv), methanesulfonamide (30 mg, 0.31 mmol, 2.0equiv), CuI (60 mg, 0.31 mmol, 3.0 equiv),trans-N,N′-Dimethylcyclohexane-1,2-diamine (45 mg, 0.31 mmol, 3.0 equiv)and K₂CO₃ (65 mg, 0.47 mmol, 3 equiv) in DMF (5 mL) was stirred at 100°C. via microwave irradiation for 2 hours under N₂ atmosphere. Themixture was diluted with 1N HCl (aq., 20 mL) and extracted with EtOAc(3*20 mL). The combined organic layers were dried over anhydrous Na₂SO₄and concentrated in vacuo. The residue was purified by flashchromatography to afford the title compound as a white solid (55 mg, 67%yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 7.92 (d, J=7.2 Hz, 1H), 7.84 (t, J=8.0 Hz,1H), 7.44 (t, J=8.0 Hz, 1H), 6.84 (d, J=8.4 Hz, 2H), 6.79 (d, J=8.0 Hz,1H), 3.56 (s, 6H), 3.39 (q, J=7.2 Hz, 2H), 3.06 (s, 3H), 2.83 (d, J=7.2Hz, 2H), 1.23-1.30 (m, 1H), 1.02 (t, J=7.2 Hz, 3H), 0.46-0.50 (m, 2H),0.25-0.29 (m, 2H). LC-MS: m/z 525.2 (M+H)⁺

Step A: 6-(cyclopropylethynyl)pyrazin-2-amine

To a mixture of 6-bromopyrazin-2-amine (3.48 g, 20 mmol, 1.0 equiv),ethynylcyclopropane (2.5 mL, 30 mmol, 1.5 equiv),bis(triphenylphosphine)palladium (II) chloride (1.4 g, 2 mmol, 0.1equiv), Et₃N (8.3 mL, 60 mmol, 3 equiv) in THF (10 mL) was added Cuprousiodide (380 mg, 2 mmol, 0.1 equiv) at room temperature. The resultingmixture was stirred at 80° C. for 16 hours under N₂ atmosphere in sealedtube. The reaction mixture was evaporated and the residue was purifiedby silica gel column chromatography (eluting with PE/EtOAc=20/1 ro 3/1)to afford the title compound 6-(cyclopropylethynyl)pyrazin-2-amine as abrown solid (2.6 g, 82% yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 7.79 (s, 1H), 7.71 (s, 1H), 6.51 (s, 2H),1.52-1.59 (m, 1H), 0.89-0.94 (m, 2H), 0.73-0.77 (m, 2H).

Step B: 6-(2-cyclopropylethyl)pyrazin-2-amine

To a mixture of 6-(cyclopropylethynyl)pyrazin-2-amine (2.1 g, 6.8 mmol,1.0 equiv) in THF (15 mL) and MeOH (15 mL) was added 10% Pd/C (400 mg)at room temperature. The resulting mixture was stirred at roomtemperature under hydrogen atmosphere (70 Psi) for 80 hours. The mixturewas filtered and the filtrate was concentrated in vacuo to afford thetitle compound 6-(2-cyclopropylethyl)pyrazin-2-amine as a brown solid(1.5 g, 70% yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 7.67 (s, 1H), 7.57 (s, 1H), 6.26 (s, 2H),2.56 (t, J=8.8 Hz, 2H), 1.47-1.60 (m, 2H), 0.64-0.72 (m, 1H), 0.35-0.43(m, 2H), 0.01-0.09 (m, 2H).

Step C: 3,5-dibromo-6-(2-cyclopropylethyl)pyrazin-2-amine

To a mixture of 6-(2-cyclopropylethyl)pyrazin-2-amine (400 mg, 2.45mmol, 1.0 equiv) in THF (10 mL) was added NBS (1.74 g, 9.80 mmol, 4equiv) at room temperature. The resulting mixture was stirred at roomtemperature for 3.5 hours under N₂ atmosphere. The mixture was dilutedwith ethyl acetate (70 mL), washed with Na₂SO₃ (3 mol/L, 20 mL), water(35 mL) and brine (60 mL) successively. The organic phase was dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified bysilica gel column chromatography (eluting with PE/EtOAc=20/1 to 5/1) toafford the title compound3,5-dibromo-6-(2-cyclopropylethyl)pyrazin-2-amine as a yellow solid (600mg, yield 76%).

¹H NMR (400 MHz, DMSO-d₆) δ: 6.84 (s, 2H), 2.69-2.73 (m, 2H), 1.46-1.52(m, 2H), 0.63-0.77 (m, 1H), 0.36-0.40 (m, 2H), 0.01-0.09 (m, 2H).

Example 66:N-(5-(2-cyclopropylethyl)-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

The title compound was prepared according to Example 65, step E˜H, byusing 3,5-dibromo-6-(2-cyclopropylethyl)pyrazin-2-amine in step E.

¹H NMR (400 MHz, DMSO-d₆) δ: 10.20 (s, 1H), 7.83-7.94 (m, 2H), 7.44 (t,J=8.4 Hz, 1H), 6.84 (d, J=8.4 Hz, 2H), 6.79 (d, J=8.0 Hz, 1H), 3.56 (s,6H), 3.39 (q, J=7.2 Hz, 2H), 3.10 (s, 3H), 3.02 (t, J=7.6 Hz, 2H), 1.66(dd, J=15.2, 7.2 Hz, 2H), 1.01 (t, J=7.2 Hz, 3H), 0.86-0.79 (m, 1H),0.38-0.50 (m, 2H), 0.09 (q, J=5.2 Hz, 2H). LC-MS: m/z 539.2 (M+H)⁺

N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-N-(4-methoxybenzyl)methanesulfonamide

The title compound was prepared according to Method C, step D, startingfrom6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(Example 1) by using N-(4-methoxybenzyl)methanesulfonamide (250 mg, 64%yield).

LC-MS: m/z 591.2 (M+H)⁺

Step A:N-(cyclopropylymethyl)-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-N-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyrazin-6-amine

To a solution ofN-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-N-(4-methoxybenzyl)methanesulfonamide(30 mg, 0.05 mmol, 1.0 equiv) in DMF (2 mL) was added NaH (3.0 mg, 0.076mmol, 1.5 equiv). After the mixture was stirred at room temperature for0.5 hour under N₂, (bromomethyl)cyclopropane (14 mg, 0.1 mmol, 3.0equiv) was added. The mixture was stirred at room temperature overnight.The mixture was quenched with H₂O (10 mL), extracted with EtOAc (3*15mL). The extracts were washed with water (10 mL) and brine (10 mL),dried over anhydrous MgSO₄ and concentrated in vacuo. The residue waspurified by Prep-TLC (PE/EtOAc=3/2) to afford the title compoundN-(cyclopropylmethyl)-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-N-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyrazin-6-amineas a yellow solid (23 mg, 70% yield).

LC-MS: m/z 567.3 (M+H)⁺

Example 67:N-(cyclopropylmethyl)-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-amine

To a solution ofN-(cyclopropylmethyl)-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-N-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyrazin-6-amine(20 mg, 0.03 mmol, 1.0 equiv) in DCM (5 mL) was added TFA (18 mg, 0.15mmol, 5 equiv) at 0° C. The mixture was stirred at room temperatureovernight. The mixture was concentrated to dryness. The residue waspurified by Prep-TLC (PE/EtOAc=1/1) to afford the title compound as ayellow solid (3 mg, 21% yield).

¹H NMR (400 MHz, CDCl₃) δ: 8.00 (br. s, 1H), 7.85 (s, 1H), 7.62 (t,J=8.0 Hz, 1H), 7.34 (t, J=8.4 Hz, 1H), 6.67 (d, J=8.4 Hz, 2H), 6.61 (d,J=8.0 Hz, 1H), 3.61 (s, 6H), 3.42-3.44 (m, 2H), 3.13 (d, J=6.8 Hz, 1H),1.01-1.09 (m, 4H), 0.86-0.89 (m, 1H), 0.49-0.53 (m, 2H), 0.21-0.24 (m,2H). LC-MS: m/z 447.2 (M+H)⁺

Step A: 2,4-dimethoxy-3-nitropyridine

2,4-dichloro-3-nitropyridine (10 g, 51.8 mmol, 1.0 equiv) was dissolvedin MeOH and the solution was cooled to 0° C. Then NaOMe solution (2mol/L in MeOH, 78 mL, 155.4 mmol, 3.0 equiv) was added dropwise. Thereaction solution was poured onto ice after stirred at 60° C. for 2 h.The resulting mixture was extracted with EtOAc (3*100 mL). The combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to give the title compound2,4-dimethoxy-3-nitropyridine as a light yellow solid (9.0 g, 94%yield). The crude product was used in next step without purification.

LC-MS: m/z 185.0 (M+H)⁺

Step B: 2,4-dimethoxypyridin-3-amine

2,4-dimethoxy-3-nitropyridine (9.0 g, 48.6 mmol, 1.0 equiv) wasdissolved in MeOH and 10% Pd/C (1.8 g) was added. The mixture wasstirred overnight under 50 psi H₂ atmosphere at room temperature. Themixture was filtered and the filter cake was swashed with MeOH (3*50mL). The filtrate was concentrated to give 2,4-dimethoxypyridin-3-amineas a gray solid (7.5 g, 99% yield). The crude product was used in nextstep directly.

LC-MS: m/z 155.1 (M+H)⁺

Example 68:N-(1-(2,4-dimethoxypyridin-3-yl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

The title compound was prepared according to Method E by using2,4-dimethoxypyridin-3-amine in step A.

¹H NMR (400 MHz, DMSO-d₆) δ: 11.16 (br. s, 1H), 8.26 (s, 1H), 8.24 (d,J=6.0 Hz, 1H), 7.98 (d, J=7.2 Hz, 1H), 7.87 (t, J=8.0 Hz, 1H), 7.06 (d,J=6.0 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 3.69 (d, J=5.2 Hz, 6H), 3.42 (q,J=7.2 Hz, 2H), 3.17 (s, 3H), 1.06 (t, J=7.2 Hz, 3H). LC-MS: m/z 471.9(M+H)⁺

Step A: pyrazin-2-ylmethyl methanesulfonate

To a mixture of pyrazin-2-ylmethanol (3.0 g, 27.3 mmol, 1.0 equiv) andtriethylamine (5.1 g, 50 mmol, 1.8 equiv) in DCM (20 mL) was was addedMsCl (5.72 g, 50 mmol, 1.8 equiv) dropwise over 10 mins. The resultingmixture was stirred at room temperature for 2 hours. Then the mixturewas diluted with water and extracted with DCM (3*30 mL). The organiclayers were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo to give the title compound as a yellow oil(assumed 100% yield). The crude compound was used in the next stepwithout any further purification. LC-MS: m/z 189.0 (M+H)⁺

Step B: S-(pyrazin-2-ylmethyl) ethanethioate

To the solution of pyrazin-2-ylmethyl methanesulfonate (5.1 g, 27.3mmol, 1.0 equiv) in acetone (40 mL) was added potassium thioacetate (4.7g, 40.9 mmol, 1.5 equiv) in one portion, the resulting mixture wasstirred at 60° C. overnight. Then the mixture was filtered and thefiltrate was concentrated in vacuo. The residue was purified by columnchromatography (eluting with PE/EtOAc=1/1) to give the title compoundS-(pyrazin-2-ylmethyl) ethanethioate as a yellow oil (3.6 g, 79% yieldin two steps). LC-MS: m/z 169.0 (M+H)⁺

Step C: pyrazin-2-ylmethanethiol

To a solution of S-(pyrazin-2-ylmethyl) ethanethioate (1.0 g, 5.95 mmol,1.0 equiv) in THF (15 mL) was added KOH (1.0 g, 17.8 mmol, 3 equiv) inwater (50 mL). The mixture was stirred at room temperature for 1 h. Thereaction mixture was acidified with 1 N HCl (aq.) and extracted with DCM(3*15 mL). The combined organic phase was used directly in next step.LC-MS: m/z 127.0 (M+H)⁺

Step D: pyrazin-2-ylmethanesulfonyl chloride

Sodium hypochlorite (26.6 mL, 35.7 mmol, 6.0 equiv) was added dropwisewith rapid stirring to a solution of pyrazin-2-ylmethanethiol (750 mg,5.95 mmol, 1.0 equiv) in DCM (45 mL) and 1N HCl (35.7 mL, 35.7 mmol, 6.0equiv) at −20° C. After the addition was completed, the mixture wasstirred at −20° C. for 2 h. The organic layer were separated and useddirectly in next step.

Step E: pyrazin-2-ylmethanesulfonamide

The solution of pyrimidine-2-sulfonyl chloride in DCM (45 mL) was addedto NH₄OH (aq., 34%, 40 mL) at 0° C. The resulting mixture was allowed toslowly warm to room temperature and stirred for 1 h. The mixture wasconcentrated under vacuum and the residue was purified by silica gelchromatography (eluting with DCM/MeOH=20/1) to afford the title compoundpyrazin-2-ylmethanesulfonamide as a light yellow solid (180 mg, 17%yield in three steps).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.68-8.74 (m, 1H), 8.63-8.68 (m, 1H),8.60-8.64 (m, 1H), 7.04 (s, 2H), 4.52 (s, 2H). LC-MS: m/z 174.0 (M+H)⁺

Example 69:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(pyrazin-2-yl)methanesulfonamide

The title compound was prepared according to Method C, step D, startingfromN-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamideby using pyrazin-2-ylmethanesulfonamide (45 mg, 48% yield). ¹H NMR (400MHz, DMSO-d₆) δ: 11.21 (s, 1H), 8.59-8.62 (m, 1H), 8.56-8.58 (m, 1H),8.46-8.50 (m, 1H), 8.21 (s, 1H), 7.97 (d, J=7.6 Hz, 1H), 7.87 (t, J=7.6Hz, 1H), 7.47 (t, J=8.4 Hz, 1H), 6.87 (d, J=8.4 Hz, 2H), 6.83 (dd,J=7.6, 0.8 Hz, 1H), 4.93 (s, 2H), 3.57 (s, 6H), 3.40 (q, J=7.2 Hz, 3H),1.03 (t, J=7.2 Hz, 3H). LC-MS: m/z 549.2 (M+H)⁺

Step A: N-(2,4-Dimethoxybenzyl)methanesulfonamide

A solution of (2,4-dimethoxyphenyl)methanamine (5.00 g, 29.9 mmol, 1.0equiv) in DCM (50 mL) was cooled to 0° C. Then triethyl amine (6.10 g,8.38 mL, 59.8 mmol, 2.0 equiv) and methanesulfonyl chloride (4.10 g,35.9 mmol, 1.2 equiv) were added to the solution at 0° C. The mixturewas stirred at room temperature overnight. The reaction mixture waspoured onto sat. NaHCO₃ solution (60 mL) and extracted with DCM (60mL*2). The combined organic layers were washed with 0.5 M HCl (aq., 60mL), dried over Na₂SO₄, filtered and concentrated in vacuo to affordN-(2,4-dimethoxybenzyl)methanesulfonamide as la ight yellow solid (7.30g, 99% yield). ¹H NMR (400 MHz, Chloroform-d) S: 7.17 (d, J=8.0 Hz, 1H),6.47 (d, J=2.4 Hz, 1H), 6.44 (dd, J=8.0, 2.4 Hz, 1H), 5.00 (t, J=6.4 Hz,1H), 4.24 (d, J=6.4 Hz, 2H), 3.84 (s, 3H), 3.80 (s, 3H), 2.73 (s, 3H).

Step B: N-(2,4-Dimethoxybenzyl)-2-hydroxy-2-methylpropane-1-sulfonamide

A solution of N-(2,4-dimethoxybenzyl)methanesulfonamide (1.50 g, 6.10mmol, 1.0 equiv) in anhydrous THF (6 mL) was cooled to −78° C. n-BuLi(5.40 mL, 13.5 mmol, 2.5 M in hexane, 2.2 equiv) was added to thesolution dropwise at −78° C. After the resulting mixture was stirred at−78° C. for 30 minutes, acetone (1.10 g, 1.40 mL, 18.3 mmol, 3.0 equiv)was added. The reaction mixture was warmed up to room temperature andstirred for 10 minutes. Then the mixture was poured onto sat. NH₄Clsolution (30 mL) and extracted with EtOAc (30 mL*2). The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel (eluted with PE/EtOAc=10/1˜4/1) to affordN-(2,4-dimethoxybenzyl)-2-hydroxy-2-methylpropane-1-sulfonamide as acolorless oil (580 mg, 31% yield). ¹H NMR (400 MHz, Chloroform-d) S:7.17 (d, J=8.0 Hz, 1H), 6.48 (d, J=2.4 Hz, 1H), 6.46 (dd, J=8.0, 2.4 Hz,1H), 5.00 (t, J=5.2 Hz, 1H), 4.24 (d, J=6.0 Hz, 2H), 3.84 (s, 3H), 3.81(s, 3H), 3.35 (s, 1H), 3.01 (s, 2H), 1.32 (s, 6H).

Step C: 2-Hydroxy-2-methylpropane-1-sulfonamide

A solution ofN-(2,4-dimethoxybenzyl)-2-hydroxy-2-methylpropane-1-sulfonamide (380 mg,1.25 mmol) in DCM (10 mL) was cooled to 0° C. and then TFA (0.5 mL) wasadded to the solution. The mixture was stirred at room temperature for 2hours. The reaction mixture was diluted with DCM (20 mL) and filtered.The filtrate was concentrated in vacuo. The residue was stirred inDCM/hexane (15 mL/15 mL) at room temperature for 1 hour. Then theresulting mixture was filtered. The filter cake was washed with hexaneto give 2-hydroxy-2-methylpropane-1-sulfonamide as a white solid (220mg, 90% yield). ¹H NMR (400 MHz, DMSO-d₆) δ: 6.72 (s, 2H), 4.79 (s, 1H),3.15 (s, 2H), 1.29 (s, 6H).

Example 70:N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-2-hydroxy-2-methylpropane-1-sulfonamide

The title compound was prepared according to Method C, Step D, startingfrom6-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using 2-hydroxy-2-methylpropane-1-sulfonamide. ¹H NMR (400 MHz,DMSO-d₆) δ: 8.17 (s, 1H), 7.90 (d, J=7.2 Hz, 1H), 7.82 (t, J=7.6 Hz,1H), 7.42 (t, J=8.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 2H), 6.77 (d, J=8.0 Hz,1H), 3.58 (s, 6H), 3.35-3.41 (m, 4H), 1.18 (s, 6H), 1.02 (t, J=7.2 Hz,3H). LC-MS: m/z 529.2 (M+H)⁺.

Step A: 4-((Benzo[d]thiazol-2-ylthio)methyl)-1-methylpiperidin-2-one

To a solution of 4-(hydroxymethyl)-1-methylpiperidin-2-one (600 mg, 4.20mmol, 1.0 equiv), benzo[d]thiazole-2-thiol (912 mg, 5.50 mmol, 1.3equiv) and PPh₃ (1.65 g, 6.30 mmol, 1.5 equiv) in anhydrous THF (25 mL)was added DEAD (1.1 g, 6.3 mmol, 1.5 equiv) at 0° C. The resultingmixture was stirred at room temperature for 16 hours. The mixture wasconcentrated in vacuo and the residue was purified by flashchromatography (eluted with DCM/MeOH=30/1) to afford4-((benzo[d]thiazol-2-ylthio)methyl)-1-methylpiperidin-2-one as a whitesolid (1.00 g, 86% yield). LC-MS: m/z 293.1 (M+H)⁺

Step B: 4-((Benzo[d]thiazol-2-ylsulfonyl)methyl)-1-methylpiperidin-2-one

To a suspension of4-((benzo[d]thiazol-2-ylthio)methyl)-1-methylpiperidin-2-one (1.1 g, 3.8mmol, 1.0 equiv) in DCM (20 mL) was added m-CPBA (1.85 g, 9.1 mmol, 2.4equiv). The mixture was stirred at room temperature for 16 hours. Themixture was washed with aqueous Na₂SO₃ solution, aqueous Na₂CO₃ solutionand brine. The organic phase was concentrated in vacuo and the residuewas purified by flash chromatography (eluted with DCM/MeOH=30/1) toafford the title compound as a white solid (800 mg, 72% yield). LC-MS:m/z 325.1 (M+H)⁺

Step C: (1-Methyl-2-oxopiperidin-4-yl)methanesulfonamide

To a suspension of4-((benzo[d]thiazol-2-ylsulfonyl)methyl)-1-methylpiperidin-2-one (400mg, 1.2 mmol, 1.0 equiv) in MeOH (10 mL) was added K₂CO₃ (840 mg, 6.10mmol, 5.0 equiv). The resulting mixture was stirred at room temperaturefor 10 minutes. Then a solution of NH₂OSO₃H (330 mg, 2.9 mmol, 2.4equiv) in H₂O (2 mL) was added. The mixture was stirred at roomtemperature for 16 hours. The resulting mixture was concentrated invacuo and the residue was purified by reverse phase prep-HPLC (elutedwith CH₃CN/H₂O=5/95˜90/10) to afford the title compound(1-methyl-2-oxopiperidin-4-yl)methanesulfonamide as a white solid (190mg, 75% yield). ¹H NMR (400 MHz, DMSO-d₆) δ: 6.97 (s, 2H), 3.24-3.28 (m,2H), 2.94-3.06 (m, 2H), 2.79 (s, 3H), 2.44-2.50 (m, 1H), 2.32-2.34 (m,1H), 2.00-2.12 (m, 2H), 1.58-1.62 (m, 1H). LC-MS: m/z 207.1 (M+H)⁺

Example 71:(S)—N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(1-methyl-2-oxopiperidin-4-yl)methanesulfonamide

The title compound was prepared according to Method C, step D, startingfrom6-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using (1-methyl-2-oxopiperidin-4-yl)methanesulfonamide and separatedby chiral separation.

¹H NMR (400 MHz, Chloroform-d) δ: 8.41 (s, 1H), 8.12 (d, J=7.2 Hz, 1H),7.68 (t, J=7.6 Hz 1H), 7.46 (s, 1H), 7.38 (t, J=7.6 Hz, 1H), 6.68-6.72(m, 3H), 3.62 (s, 3H), 3.61 (s, 3H), 3.42 (q, J=7.6 Hz, 2H), 3.38-3.22(m, 4H), 2.93 (s, 3H), 2.52-2.46 (m, 2H), 2.16-2.10 (m, 1H), 1.98-2.02(m, 1H), 1.22-1.26 (m, 1H), 1.07 (t, J=7.6 Hz, 3H). LC-MS: m/z 582.2(M+H)⁺

Example 72:(R)—N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(1-methyl-2-oxopiperidin-4-yl)methanesulfonamide

The tile compound was prepared according to Method C, step D, startingfrom6-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using (1-methyl-2-oxopiperidin-4-yl)methanesulfonamide and separatedby chiral separation. ¹H NMR (400 MHz, Chloroform-d) δ: 8.41 (s, 1H),8.12 (d, J=7.2 Hz, 1H), 7.68 (t, J=7.6 Hz 1H), 7.46 (s, 1H), 7.38 (t,J=7.6 Hz, 1H), 6.68-6.72 (m, 3H), 3.62 (s, 3H), 3.61 (s, 3H), 3.42 (q,J=7.6 Hz, 2H), 3.38-3.22 (m, 4H), 2.93 (s, 3H), 2.52-2.46 (m, 2H),2.16-2.10 (m, 1H), 1.98-2.02 (m, 1H), 1.22-1.26 (m, 1H), 1.07 (t, J=7.6Hz, 3H). LC-MS: m/z 582.2 (M+H)⁺

Step A: pyrrolidine-1-sulfonamide

To a solution of pyrrolidine (3.30 g, 42.3 mmol, 1.0 equiv) in dioxane(100 mL) was added sulfuric diamide (10.0 g, 104 mmol, 2.5 equiv). Thereaction mixture was stirred at 110° C. for 16 hours. The reactionmixture was concentrated in vacuo, reslurried in DCM and filtered toafford pyrrolidine-1-sulfonamide as a white solid (5.00 g, 71% yield).¹H NMR (400 MHz, DMSO-d₆) δ: 6.62 (s, 2H), 3.08-3.10 (m, 4H) 1.78-1.80(m, 4H). LC-MS: m/z 151.1 (M+H)⁺

Example 73:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)pyrrolidine-1-sulfonamide

The title compound was prepared according to Method C, step D, startingfrom6-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using pyrrolidine-1-sulfonamide. ¹H NMR (400 MHz, Chloroform-d) δ:8.35 (s, 1H), 8.13 (d, J=7.2 Hz, 1H), 7.65-7.69 (m, 1H), 7.36 (t, J=8.4Hz, 1H), 7.14 (s, 1H), 6.66-6.70 (m, 3H), 3.63 (s, 6H), 3.42 (q, J=7.2Hz, 2H), 3.26-3.30 (m, 4H), 1.63-1.67 (m, 4H), 1.08 (t, J=7.2 Hz, 3H).LC-MS: m/z 526.1 (M+H)⁺

tert-Butyl 4-sulfamoylpiperazine-1-carboxylate

The title compound was prepared according to the preparation ofpyrrolidine-1-sulfonamide by using tert-butyl piperazine-1-carboxylate.LC-MS: m/z 266.1 (M+H)⁺

tert-Butyl4-(N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)sulfamoyl)piperazine-1-carboxylate

The title compound was prepared according to Method C, step D, startingfrom6-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using tert-butyl 4-sulfamoylpiperazine-1-carboxylate. LC-MS: m/z641.2 (M+H)⁺

Example 74:N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)piperazine-1-sulfonamide

The solution of tert-butyl4-(N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)sulfamoyl)piperazine-1-carboxylate(86.0 mg, 0.1 mmol) in HCl/MeOH (4 mol/L, 2 mL) was stirred at roomtemperature for 3 hours. Then the mixture was concentrated in vacuo. Theresidue was purified by reverse phase HPLC to afford a HCl salt ofN-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)piperazine-1-sulfonamideas light yellow solid (51.0 mg, 70% yield). ¹H NMR (400 MHz, DMSO-d₆) δ:8.19 (s, 1H), 8.16 (s, 1H), 7.90 (d, J=7.6 Hz, 1H), 7.82 (t, J=8.0 Hz,1H), 7.42 (t, J=8.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 2H), 6.75 (d, J=8.0 Hz,1H), 3.59 (s, 6H), 3.32-3.40 (m, 2H), 2.96-2.98 (m, 4H), 2.72-2.76 (m,4H), 1.02 (t, J=7.2 Hz, 3H). LC-MS: m/z 541.2 (M+H)⁺

Piperidine-1-sulfonamide

The title compound was prepared according to the preparation ofpyrrolidine-1-sulfonamide by using piperidine. ¹H NMR (400 MHz,Chloroform-d) δ: 4.42 (s, 2H), 3.15 (t, J=5.2 Hz, 4H), 1.63-1.77 (m,4H), 1.47-1.59 (m, 2H).

Example 75:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)piperidine-1-sulfonamide

The title compound was prepared according to Method C, step D, startingfrom6-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using piperidine-1-sulfonamide. ¹H NMR (400 MHz, Chloroform-d) δ:8.43 (s, 1H), 8.12 (d, J=7.2 Hz, 1H), 7.64-7.70 (m, 1H), 7.37 (t, J=8.6Hz, 1H), 6.95 (s, 1H), 6.64-6.72 (m, 3H), 3.63 (s, 6H), 3.42 (q, J=7.2Hz, 2H), 3.18-3.12 (m, 4H), 1.53-1.45 (m, 4H), 1.45-1.38 (m, 2H), 1.08(t, J=7.2 Hz, 3H). LC-MS: m/z 540.2 (M+H)⁺

Example 76:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-N′,N′-dimethylsulfamide

The title compound was prepared according to Method C, step D, startingfrom6-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using N, N-dimethylsulfamide. ¹H NMR (400 MHz, DMSO-d₆) δ: 10.89 (s,1H), 8.24 (s, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.85 (t, J=7.6 Hz, 1H), 7.43(t, J=8.4 Hz, 1H), 6.84 (d, J=8.4 Hz, 2H), 6.81 (dd, J=8.0, 0.8 Hz, 1H),3.59 (s, 6H), 3.38 (t, J=7.2 Hz, 2H), 2.55 (s, 6H), 1.02 (t, J=7.2 Hz,3H). LC-MS: m/z 500.2 (M+H)⁺

Example 77:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-N′-methyl-N′-cyclopropylsulfamide

The title compound was prepared according to Method C, step D, startingfrom6-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using N-methyl-N-cyclopropylsulfamide. ¹H NMR (400 MHz, DMSO-d₆) δ:11.04 (br. s, 1H), 8.21 (s, 1H), 7.93 (d, J=7.2 Hz, 1H), 7.82 (t, J=7.6Hz, 1H), 7.40 (t, J=8.4 Hz, 1H), 6.80 (d, J=8.4 Hz, 2H), 6.77 (d, J=8.0Hz, 1H), 3.58 (s, 6H), 3.36 (q, J=7.2 Hz, 2H), 2.55 (s, 3H), 2.21-2.29(m, 1H), 1.02 (t, J=7.2 Hz, 3H), 0.48-0.59 (m, 2H), 0.36-0.46 (m, 2H).LC-MS: m/z 526.2 (M+H)⁺

Example 78:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(5-fluoropyridin-2-yl)methanesulfonamide

The title compound was prepared according to Method C, step D, startingfrom6-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using (5-fluoropyridin-2-yl)methanesulfonamide. ¹H NMR (400 MHz,DMSO-d₆) δ:11.13 (s, 1H), 8.48 (d, J=4.0 Hz, 1H), 8.18 (s, 1H),7.94-7.96 (m, 1H), 7.86 (t, J=8.0 Hz, 1H), 7.70-7.75 (m, 1H), 7.47 (t,J=8.0 Hz, 1H), 7.29 (dd, J=8.0, 4.0 Hz, 1H), 6.87 (d, J=8.0 Hz, 2H),6.82-6.84 (m, 1H), 4.84 (s, 2H), 3.56 (s, 6H), 3.40 (q, J=7.2 Hz, 2H),1.03 (t, J=7.2 Hz, 3H). LC-MS: m/z 566.2 (M+H)⁺

Example 79:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(5-fluoropyrimidin-2-yl)methanesulfonamide

The title compound was prepared according to Method C, step D, startingfrom6-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using (5-fluoropyrimidin-2-yl)methanesulfonamide. ¹H NMR (400 MHz,CD₃OD) δ: 8.63 (s, 2H), 8.19 (s, 1H), 7.89 (d, J=7.2 Hz, 1H), 7.78 (t,J=7.6 Hz, 1H), 7.45 (t, J=8.4 Hz, 1H), 6.82 (d, J=8.4 Hz, 2H), 6.76 (dd,J=8.4, 0.4 Hz, 1H), 4.95 (s, 2H), 3.62 (s, 6H), 3.48 (q, J=7.2 Hz, 2H),1.07 (t, J=7.2 Hz, 3H). LC-MS: m/z 567.1 (M+H)⁺

Example 80:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(5-methylpyrimidin-2-yl)methanesulfonamide

The title compound was prepared according to Method C, step D, startingfrom6-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using (5-methylpyrimidin-2-yl)methanesulfonamide. ¹H NMR (400 MHz,DMSO-d₆) δ: 11.13 (s, 1H), 8.58 (s, 2H), 8.18 (s, 1H), 7.93 (d, J=7.2Hz, 1H), 7.85 (t, J=7.8 Hz 1H), 7.44 (t, J=8.4 Hz, 1H), 6.85 (d, J=8.4Hz, 2H), 6.81 (d, J=8.0 Hz, 1H), 4.87 (s, 2H), 3.56 (s, 6H), 3.39 (q,J=7.2 Hz, 2H), 2.24 (s, 3H), 1.02 (t, J=7.2 Hz, 3H). LC-MS: m/z 563.1(M+H)⁺

Step A: trans-Methyl 3-hydroxy-3-methylcyclobutane-1-carboxylate

Methyl 3-oxocyclobutane-1-carboxylate (1.05 g, 8.19 mmol, 1 equiv) wasdissolved in anhydrous THF (10 mL) and cooled to −78° C. MeMgBr (3 mol/Lin diethyl ether) (8.2 mL, 24.6 mmol, 3 equiv) was added dropwise. Themixture was stirred at −20° C. for 2 hours. The reaction was quenchedwith sat. NH₄Cl solution (10 mL) and extracted with DCM (20 mL*3). Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄,filtered, concentrated and purified via column chromatography(DCM/MeOH=20/1) to give trans-methyl3-hydroxy-3-methylcyclobutane-1-carboxylate as a colorless oil (410 mg,36.7% yield). LC-MS: m/z 145.1 (M+H)⁺, 127.1 (M−OH)⁺

Step B: trans-Methyl3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutane-1-carboxylate

trans-Methyl 3-hydroxy-3-methylcyclobutane-1-carboxylate (410 mg, 2.84mmol, 1 equiv) was dissolved in DCM (5 mL). Then dihydropyran (239 mg,3.41 mmol, 0.258 mL, 1.2 equiv) and pyridinium 4-toluenesulfonate (142mg, 0.568 mmol, 0.2 equiv) were added. The solution was stirred at roomtemperature for 4 hours. The mixture was diluted with 20 mL ethylacetate and washed with water, brine, dried over anhydrous Na₂SO₄,filtered, concentrated and purified via column chromatography (elutedwith PE/EtOAc=20/1) to give trans-methyl3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutane-1-carboxylate asclear oil (240 mg, 37% yield). ¹H NMR (400 MHz, Chloroform-d) δ:4.68-4.70 (m, 1H), 3.85-3.91 (m, 1H), 3.61 (s, 3H), 3.39-3.44 (m, 1H),2.59-2.68 (m, 1H), 2.41-2.49 (m, 2H), 2.07-2.16 (m, 2H), 1.55-1.84 (m,6H), 1.35 (s, 3H).

Step C:trans-(3-Methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methanol

The solution of trans-methyl3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutane-1-carboxylate (240mg, 1.05 mmol, 1 equiv) in anhydrous THF (5 mL) was cooled to 0° C. 2.1mL LiAlH₄ solution (1 moL/L in THF, 2.10 mmol, 2 equiv) was addeddropwise. The mixture was stirred at 0° C. for 2 hours. The reaction wasquenched with 1 mL water and extracted with DCM (5 mL*3). The organiclayers were washed with brine, dried over anhydrous Na₂SO₄, filtered,concentrated and purified via column chromatography (eluted withPE/EtOAc=2/1) to givetrans-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methanol ascolorless oil (120 mg, 57% yield). ¹H NMR (400 MHz, Chloroform-d) δ:4.62-4.64 (m, 1H), 3.86-3.91 (m, 1H), 3.56 (d, J=5.6 Hz, 2H), 3.37-3.42(m, 1H), 1.78-2.15 (m, 9H), 1.59-1.6 (m, 2H), 1.34 (s, 3H).

Step D:trans-2-(((3-Methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)thio)benzo[d]thiazole

trans-(3-Methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methanol(120 mg, 0.599 mmol, 1 equiv), benzo[d]thiazole-2-thiol (120 mg, 0.719mmol, 1.2 equiv), and PPh₃ (188 mg, 0.719 mmol, 1.2 equiv) weredissolved in anhydrous THF (5 mL) and cooled to −78° C. Then DIAD (145mg, 0.142 mL, 0.719 mmol, 1.2 equiv) was added dropwise. The reactionmixture was stirred at room temperature overnight. The reaction mixturewas concentrated and purified via column chromatography (eluted withPE/EtOAc=10/1) to givetrans-2-(((3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)thio)benzo[d]thiazoleas colorless oil (150 mg, 72% yield). ¹H NMR (400 MHz, Chloroform-d) δ:7.79 (d, J=7.6 Hz, 1H), 7.68 (dd, J=8.0, 0.8 Hz, 1H), 7.34 (td, J=8.4,1.2 Hz, 1H), 7.22 (td, J=8.0, 1.2 Hz, 1H), 4.55-4.64 (m, 1H), 3.85-3.90(m, 1H), 3.36-3.41 (m, 3H), 2.24-2.32 (m, 1H), 2.01-2.18 (m, 3H),1.91-1.98 (m, 1H), 1.72-1.82 (m, 1H), 1.58-1.63 (m, 1H), 1.42-1.46 (m,4H), 1.32 (s, 3H)

Step E:trans-3-((Benzo[d]thiazol-2-ylsulfonyl)methyl)-1-methylcyclobutan-1-ol

trans-2-(((3-Methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)thio)benzo[d]thiazole(150 mg, 0.429 mmol, 1 equiv) was dissolved in DCM (10 mL) and m-CPBA(190 mg, 85% purity, 0.944 mmol, 2.2 equiv) was added partially. Themixture was stirred overnight at room temperature and diluted with DCM(10 mL), washed with sat. Na₂S₂O₃ solution, sat. NaHCO₃ solution, brine,dried over anhydrous Na₂SO₄, filtered, concentrated and purified viacolumn chromatography (eluted with PE/EtOAc=4/1) to givetrans-3-((benzo[d]thiazol-2-ylsulfonyl)methyl)-1-methylcyclobutan-1-olas white solid (100 mg, 78% yield). LC-MS: m/z 298.1 (M+H)⁺

Step F:trans-2-(((3-Methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)sulfonyl)benzo[d]thiazole

To a solution oftrans-3-((benzo[d]thiazol-2-ylsulfonyl)methyl)-1-methylcyclobutan-1-ol(420 mg, 1.41 mmol, 1 equiv) in DCM (5 mL) were added dihydropyran (225mg, 2.68 mmol, 1.9 equiv) and PPTS (67.3 mg, 0.268 mmol, 0.19 equiv).The mixture was stirred at room temperature overnight. Then the mixturewas diluted with EtOAc (20 mL) and washed with brine. The organic layerwas dried over Na₂SO₄, concentrated and purified via columnchromatography (eluted with PE/EtOAc=5/1) to givetrans-2-(((3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)sulfonyl)benzo[d]thiazoleas a white solid (180 mg, 34% yield). ¹H NMR (400 MHz, Chloroform-d) δ:8.15 (d, J=8.4 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H), 7.51-7.60 (m, 2H),4.49-4.56 (m, 1H), 3.79-3.84 (m, 1H), 3.60 (d, J=7.6 Hz, 2H), 3.31-3.36(m, 1H), 2.39-2.48 (m, 2H), 2.05-2.14 (m, 3H), 1.90-1.95 (m, 1H),1.51-1.70 (m, 5H), 1.29 (s, 3H).

Step G:trans-(3-Methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methanesulfonamide

trans-2-(((3-Methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methyl)sulfonyl)benzo[d]thiazole(2.80 g, 7.34 mmol, 1.0 equiv) was dissolved in MeOH (20 mL) and K₂CO₃(1.53 g, 11.1 mmol) was added. The mixture was stirred at roomtemperature for 1.5 h. The mixture was concentrated, diluted with H₂O(40 mL), and washed with EtOAc (20 mL). The aqueous phase wasfreeze-dried in vacuo to get a white to yellow solid. The solid wassuspended in MeOH (8 mL) and K₂CO₃ (3.04 g, 22.0 mmol, 3.0 equiv) wasadded. NH₂OSO₃H (1.07 g, 9.54 mmol, 1.3 equiv) was dissolved in H₂O (7mL) and added into the mixture slowly. The mixture was stirred at roomtemperature overnight. Then MeOH was removed and the reaction mixturewas extracted with DCM (20 mL*3). The organic layer was washed withbrine, dried over Na₂SO₄, concentrated and purified via columnchromatography (eluted with PE/EtOAc=2/1) to givetrans-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methanesulfonamideas light yellow oil (1.14 g, 59% yield). ¹H NMR (400 MHz, Chloroform-d)δ: 4.55-4.64 (m, 3H), 3.85-3.89 (m, 1H), 3.36-3.42 (m, 1H), 3.20 (d,J=7.2 Hz, 2H), 3.31-3.36 (m, 1H), 2.08-2.26 (m, 3H), 1.97-2.02 (m, 1H),1.73-1.82 (m, 1H), 1.58-1.63 (m, 1H), 1.44-1.46 (m, 4H), 1.35 (s, 3H).

Step H:trans-N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-((1r,3r)-3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methanesulfonamide

The title compound was prepared according to Method C, step D, startingfrom6-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby usingtrans-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methanesulfonamide.LC-MS: m/z 639.2 (M+H)⁺

Step I:trans-N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)methanesulfonamide (Example 81)

A solution oftrans-N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-((1r,3r)-3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)cyclobutyl)methanesulfonamide(150 mg, 0.235 mmol) in HCOOH (5 mL) was stirred at room temperatureovernight. The mixture was concentrated in vacuo and the residue waspurified by prep-TLC (eluted with DCM/MeOH=20/1) and reverse phaseprep-HPLC (eluted with CH₃CN/H₂O=5/95˜95/5 including 0.1% HCOOH) toafford ttrans-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)methanesulfonamide as a light yellowsolid (62.0 mg, 47% yield). ¹H NMR (400 MHz, Chloroform-d) δ: 8.50 (s,1H), 8.13 (d, J=7.2 Hz, 1H), 7.69 (t, J=7.6 Hz, 1H), 7.40 (t, J=8.4 Hz,1H), 6.96 (s, 1H), 6.69-6.72 (m, 3H), 3.62 (s, 6H), 3.39-3.45 (m, 4H),2.25-2.37 (m, 3H), 1.76-1.85 (m, 2H), 1.34 (s, 3H), 1.08 (t, J=7.2 Hz,3H). LC-MS: m/z 555.2 (M+H)⁺

Step A: Sodium but-2-yne-1-sulfonate

To a solution of Na₂SO₃ (947 mg, 7.5 mmol, 1.0 equiv) in H₂O (10 mL) wasadded 1-bromobut-2-yne (1.0 g, 7.5 mmol, 1.0 equiv) at room temperature.The mixture was stirred at 20° C. for 0.5 hour. The mixture was stirredat 60° C. for 1.5 hours and evaporated to dryness under reduced pressureto give the crude sodium salt of but-2-yne-1-sulfonate as a white solid(1.95 g, crude). LC-MS: m/z 156.9 (M+H)⁺

Step B: But-2-yne-1-sulfonamide

To a suspension of but-2-yne-1-sulfonate sodium salt (200 mg crude, 0.77mmol, 1.0 equiv) in DCM (5 mL) was added (COCl)₂ (163 mg, 1.28 mmol, 1.7equiv) at 0° C. under N₂. The mixture was stirred at room temperaturefor 4 hours. The mixture was added to a solution of NH₄OH (5 mL) inacetone (5 mL) at 0° C. The resulting mixture was stirred at 0° C. for 1hour. The mixture was concentrated under vacuum. The residue was stirredin EtOAc (20 mL) for 5 minutes and filtered. The filtrate wasconcentrated in vacuo. The new residue was purified by flashchromatography on silica gel (PE/EtOAc=3/1) to givebut-2-yne-1-sulfonamide as a white solid (58.0 mg, 57% yield). ¹H NMR(400 MHz, DMSO-d₆) δ: 7.04 (s, 2H), 3.91 (q, J=2.4 Hz, 2H), 1.84 (t,J=2.4 Hz, 3H).

Example 82:N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)but-2-yne-1-sulfonamide

The title compound was prepared according to Method C, step D, startingfrom6-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using but-2-yne-1-sulfonamide. ¹H NMR (400 MHz, Chloroform-d) δ: 8.62(s, 1H), 8.12 (d, J=7.6 Hz, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.39 (t, J=8.4Hz, 1H), 7.18 (s, 1H), 6.68-6.71 (m, 3H), 4.09 (q, J=2.4 Hz, 2H), 3.62(s, 6H), 3.43 (q, J=7.2 Hz, 2H), 1.71 (t, J=2.4 Hz, 3H), 1.08 (t, J=7.2Hz, 3H). LC-MS: m/z 509.2 (M+H)⁺

Example 83:N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(5-methylpyridin-2-yl)methanesulfonamide

The title compound was prepared according to Method C, step D, startingfrom6-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using (5-methylpyridin-2-yl)methanesulfonamide. ¹H NMR (400 MHz,Chloroform-d) &: 8.42 (s, 1H), 8.29 (s, 1H), 8.10 (d, J=7.6 Hz, 1H),7.67 (dd, J=8.4, 7.6 Hz, 1H), 7.37-7.47 (m, 2H), 7.24 (d, J=8.0 Hz, 1H),6.64-6.74 (m, 3H), 4.66 (s, 2H), 3.59 (s, 6H), 3.42 (q, J=7.2 Hz, 2H),2.23 (s, 3H), 1.08 (t, J=7.2 Hz, 3H). LC-MS: m/z 562.2 (M+H)⁺

Example 84:N-(1-(2,4-Dimethoxypyridin-3-yl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

The title compound was an atropisomer of Example 68 obtained by chiralseparation. The absolute configuration was arbitrarily assigned. ¹H NMR(400 MHz, Chloroform-d) δ: 8.53 (s, 1H), 8.21 (d, J=6.0 Hz, 1H), 8.16(d, J=7.2 Hz, 1H), 7.71 (t, J=8.0 Hz, 1H), 7.00 (s, 1H), 6.78-6.70 (m,2H), 3.81 (s, 3H), 3.72 (s, 3H), 3.54-3.38 (m, 2H), 3.19 (s, 3H), 1.14(t, J=7.2 Hz, 3H). LC-MS: m/z 472.1 (M+H)⁺

Example 85:N-(1-(2,4-Dimethoxypyridin-3-yl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

The title compound was an atropisomer of Example 68 obtained by chiralseparation. The absolute configuration was arbitrarily assigned. H NMR(400 MHz, Chloroform-d) δ: 8.56 (s, 1H), 8.25 (d, J=5.6 Hz, 1H), 8.19(d, J=7.6 Hz, 1H), 7.72 (t, J=8.0 Hz, 1H), 7.13 (s, 1H), 6.81-6.72 (m,2H), 3.87 (s, 3H), 3.75 (s, 3H), 3.54-3.39 (m, 2H), 3.20 (s, 3H), 1.15(t, J=7.2 Hz, 3H). LC-MS: m/z 472.1 (M+H)⁺

Method I

Step A: 6-Ethylpyrazin-2-amine

To a mixture of 6-chloropyrazin-2-amine (10.0 g, 77.2 mmol, 1.0 equiv)and Ni(dppp)Cl₂ (4.18 g, 7.72 mmol, 0.1 equiv) in anhydrous dioxane (80mL) at 0° C. was added Et₂Zn (2 mol/L in hexane, 77.0 mL, 154 mmol, 2.0equiv) under N₂ atmosphere. The reaction mixture was refluxed overnight.The reaction was quenched with MeOH and concentrated in vacuo. Theresidue was partitioned between EtOAc and brine. The organic phase wasdried over Na₂SO₄, filtered and evaporated. The residue was purified byflash chromatography (eluted with PE/EtOAc=2/1) to give6-ethylpyrazin-2-amine as a yellow solid. (3.57 g, 37% yield). LC-MS:m/z 124.1 (M+H)⁺

Step B: 3,5-Dibromo-6-ethylpyrazin-2-amine

To a mixture of 6-ethylpyrazin-2-amine (3.57 g, 29.0 mmol, 1.0 equiv) inTHF (50 mL) was added NBS (20.7 g, 116 mmol, 4.0 equiv) at 0° C. Theresulting mixture was stirred at room temperature for 3 hours. Themixture was diluted with EtOAc (100 mL) and washed with saturated Na₂SO₃aqueous solution and brine, dried over anhydrous Na₂SO₄ and concentratedin vacuo. The residue was purified by column chromatography on silicagel (eluted with PE/EtOAc=20/1) to afford the title compound3,5-dibromo-6-ethylpyrazin-2-amine as yellow oil. (6.65 g, 82% yield).LC-MS: m/z 279.8, 281.8, 283.8 (M+H)⁺

Step C: N-(3,5-Dibromo-6-ethylpyrazin-2-yl)-6-ethoxypicolinamide

To a solution of 3,5-dibromo-6-ethylpyrazin-2-amine (6.65 g, 23.7 mmol,1.0 equiv) in toluene (100 mL) was added AlMe₃ (2 mol/L in toluene, 17.8mL, 35.5 mmol, 1.50 equiv) dropwise at 0° C. under N₂ atmosphere. Afterthe mixture was stirred at 0° C. for 30 minutes and at 80° C. for 30minutes, ethyl 6-ethoxypicolinate (6.00 g, 30.8 mmol, 1.3 equiv) wasadded. The resulting mixture was stirred at 80° C. overnight. Thereaction mixture was quenched with 1N aq. HCl and extracted with DCM(200 mL*2). The combined organic layers were dried over anhydrous Na₂SO₄and concentrated in vacuo. The residue was stirred in MeOH (30 mL) for30 mins. The mixture was filtered and the filter cake affordN-(3,5-dibromo-6-ethylpyrazin-2-yl)-6-ethoxypicolinamide as a whitesolid (7.87 g, 77% yield). LC-MS: m/z 428.5, 430.5, 432.5 (M+H)⁺

Step D:N-(5-Bromo-3-((2,6-dimethoxyphenyl)amino)-6-ethylpyrazin-2-yl)-6-ethoxypicolinamide

A suspension of N-(3,5-dibromo-6-ethylpyrazin-2-yl)-6-ethoxypicolinamide(1.00 g, 2.33 mmol, 1.0 equiv), 2,6-dimethoxyaniline (536 mg, 3.50 mmol,1.5 equiv), Pd₂(dba)₃ (213 mg, 0.233 mmol, 0.1 equiv), Xantphos (270 mg,0.466 mmol, 0.2 equiv) and K₂CO₃ (805 mg, 5.83 mmol, 2.5 equiv) in1,4-dioxane (10 mL) was stirred at 120° C. via microwave irradiation for2 hours under N₂ atmosphere. The mixture was filtered through celite andthe filtrate was concentrated. The residue was purified by columnchromatography on silica gel (eluted with PE/EtOAc=20/1) to giveN-(5-bromo-3-((2,6-dimethoxyphenyl)amino)-6-ethylpyrazin-2-yl)-6-ethoxypicolinamideas a yellow solid (630 mg, 54% yield). LC-MS: m/z 501.6, 503.5 (M+H)⁺

Step E:6-Bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-5-ethyl-1H-imidazo[4,5-b]pyrazine

The solution ofN-(5-bromo-3-((2,6-dimethoxyphenyl)amino)-6-ethylpyrazin-2-yl)-6-ethoxypicolinamide(330 mg, 0.660 mmol) in AcOH (12 mL) was stirred at 120° C. viamicrowave irradiation for 2 hours. The reaction mixture was poured insat.Na₂CO₃ and extracted with DCM. The organic phase was dried overanhydrous MgSO₄ and concentrated in vacuo. The residue was washed withEtOAc/PE=1/2 to give6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-5-ethyl-1H-imidazo[4,5-b]pyrazineas a yellow solid (520 mg, 81% yield). The crude product was used innext step without further purification. LC-MS: m/z 484.0, 486.0 (M+H)⁺

Step F:N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-5-ethyl-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide(Example 86)

A suspension of6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-5-ethyl-1H-imidazo[4,5-b]pyrazine(100 mg, 0.21 mmol, 1.0 equiv), methanesulfonamide (80.0 mg, 0.840 mmol,4.0 equiv), CuI (80.0 mg, 0.420 mmol, 2.0 equiv), trans-N,N′-Dimethylcyclohexane-1, 2-diamine (60.0 mg, 0.420 mmol, 2.0 equiv) andK₂CO₃ (87.0 mg, 0.630 mmol, 3.0 equiv) in DMF (4 mL) was stirred at 110°C. via microwave irradiation for 2 hours under N₂ atmosphere. Themixture was diluted with DCM (10 mL) and filtered. The filtrate wasconcentrated. The residue was purified by prep-HPLC to giveN-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-5-ethyl-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamideas a yellow solid (46.9 mg, 46% yield). ¹H NMR (400 MHz, Chloroform-d)δ: 8.15 (d, J=7.6 Hz, 1H), 7.68 (t, J=7.6 Hz, 1H), 7.36 (t, J=8.4 Hz,1H), 6.78 (s, 1H), 6.73-6.64 (m, 3H), 3.61 (s, 6H), 3.43 (q, J=6.8 Hz,2H), 3.23 (s, 3H), 2.91 (q, J=7.6 Hz, 2H), 1.45 (t, J=7.6 Hz, 3H), 1.07(t, J=6.8 Hz, 3H). LC-MS: m/z 499.1 (M+H)⁺

Example 87:N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-5-methyl-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

The title compound was prepared according to Method I by using6-methylpyrazin-2-amine instead of 6-ethylpyrazin-2-amine in step B. ¹HNMR (400 MHz, Chloroform-d) δ: 8.10 (d, J=7.2 Hz, 1H), 7.67 (t, J=7.6cHz, 1H), 7.35 (t, J=8.4 Hz, 1H), 6.71 (d, J=10.0 Hz, 2H), 6.67 (d, J=8.4Hz, 2H), 3.61 (s, 6H), 3.42 (q, J=7.2 Hz, 2H), 3.23 (s, 3H), 2.66 (s,3H), 1.07 (t, J=7.2 Hz, 3H). LC-MS: m/z 485.1 (M+H)⁺

Step A: (Cyclobutylmethyl)magnesium bromide

To a solution of Mg (1.60 g, 67.5 mmol, 1.5 equiv) and 12 (three pieces)in THF (40 mL) was added (bromomethyl)cyclobutane (1.10 mL, 12.0 mmol,0.25 equiv). The mixture was heated to initiate the reaction. Then(bromomethyl)cyclobutane (3.5 mL, 33 mmol, 0.75 equiv) was added. Themixture was stirred at room temperature for 16 hours. The reactionmixture was used for the next step directly.

Step B: (6-(Cyclobutylmethyl)pyrazin-2-yl)-bis-carbamic acid tert-butylester

To a solution of (6-chloropyrazin-2-yl)-bis-carbamic acid tert-butylester (5.00 g, 15.0 mmol, 1 equiv) and Fe(acac)₃ (265 mg, 0.750 mmol,0.05 equiv) in NMP/THF (5 mL/50 mL) was added(cyclobutylmethyl)magnesium bromide solution of last step at 0° C. Thereaction mixture was stirred at room temperature for 16 hours. Thereaction mixture was diluted with EtOAc and filtered. The organic phasewas purified by flash chromatography (eluted with PE/EtOAc=10/1) toafford (6-(cyclobutylmethyl)pyrazin-2-yl)-bis-carbamic acid tert-butylester as white solid (2.40 g, 53% yield). LC-MS: m/z 364.2 (M+H)⁺

Step C: 6-(Cyclobutylmethyl)pyrazin-2-amine

A suspension of (6-(cyclobutylmethyl)pyrazin-2-yl)-bis-carbamic acidtert-butyl ester (2.00 g, 7.60 mmol, 1.0 equiv) in MeOH (40 mL) wasadded HCl/dioxane (4 mol/L, 20 mL) at 0° C. The mixture was stirred atroom temperature for 16 hours. The reaction mixture was concentratedthen diluted with EtOAc and washed with 4 N NaHCO₃ aq. solution. Theorganic phase was concentrated and purified by flash chromatography(PE/EtOAc=1/1) to afford 6-(cyclobutylmethyl)pyrazin-2-amine as a whitesolid (770 mg, 77% yield). LC-MS: m/z 164.1 (M+H)⁺

Example 88:N-(5-(Cyclobutylmethyl)-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

The title compound was prepared according to Method I by using6-(cyclobutylmethyl)pyrazin-2-amine instead of 6-ethylpyrazin-2-amine instep B. ¹H NMR (400 MHz, Chloroform-d) δ: 8.12 (d, J=7.2 Hz, 1H), 7.67(t, J=8.4 Hz, 1H), 7.35 (t, J=8.4 Hz, 1H), 6.84 (s, 1H), 6.66-6.69 (m,3H), 3.60 (s, 6H), 3.43 (q, J=7.2 Hz, 2H), 3.24 (s, 3H), 2.92-3.02 (m,3H), 2.16-2.20 (m, 2H), 1.80-1.92 (m, 4H), 1.06 (t, J=7.2 Hz, 3H).LC-MS: m/z 539.2 (M+H)⁺

Step A: 2-Chloro-6-cyclopropoxypyrazine

To a solution of cyclopropanol (3.84 g, 66.2 mmol, 1.5 equiv) in THF (80mL) was added NaH (60% in mineral oil, 2.64 g, 66.2 mmol, 1.5 equiv) at0° C. The mixture was stirred at 0° C. for 15 minutes. A solution of2,6-dichloropyrazine (6.57 g, 44.1 mmol, 1.0 equiv) was added. Themixture was stirred at 0° C. for 30 minutes, and then warmed up to roomtemperature and stirred for another 1 hour. The reaction was quenched byadding saturated NH₄Cl solution (50 mL) and extracted with EtOAc (50mL*3). The combined organic phase was washed with brine (30 mL), driedover anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by flash chromatography on silica gel (eluted withPE/EtOAc=20/1) to afford the title compound2-chloro-6-cyclopropoxypyrazine as a white solid (6.19 g, 82% yield). ¹HNMR (400 MHz, Chloroform-d) δ: 8.11 (s, 1H), 8.04 (s, 1H), 4.23 (tt,J=6.4, 3.2 Hz, 1H), 0.81-0.72 (m, 4H). LC-MS: m/z 171.0 (M+H)⁺

Step B: 6-Cyclopropoxy-N-(4-methoxybenzyl)pyrazin-2-amine

A solution of 2-chloro-6-cyclopropoxypyrazine (2.00 g, 11.8 mmol, 1.0equiv) in PMBNH₂ (10 mL) was charged into a sealed tube The mixture wasstirred at 160° C. via microwave irradiation for 2 hours. The mixturewas purified by flash chromatography on silica gel (eluted withPE/EtOAc=1/1) to afford the title compound6-cyclopropoxy-N-(4-methoxybenzyl)pyrazin-2-amine as a yellow solid(2.67 g, 83% yield). LC-MS: m/z 272.1 (M+H)⁺

Step C: 6-Cyclopropoxypyrazin-2-amine

A solution of 6-cyclopropoxy-N-(4-methoxybenzyl)pyrazin-2-amine (2.67 g,9.90 mmol, 1.0 equiv) in TFA (50 mL) was stirred at 60° C. overnight.The solvent was distilled off under vacuum. The residue was redissolvedin DCM (50 mL) and washed with saturated NaHCO₃ solution (50 mL*3). Theorganic layer was dried over Na₂SO₄ and concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel (eluted withPE/EtOAc=1/1) to afford the title compound 6-cyclopropoxypyrazin-2-amineas a yellow solid (1.46 g, 97% yield). ¹H NMR (400 MHz, DMSO-d₆) δ: 7.48(s, 1H), 7.36 (s, 1H), 6.37 (s, 2H), 4.10 (tt, J=6.4, 3.2 Hz, 1H),0.78-0.68 (m, 2H), 0.71-0.61 (m, 2H). LC-MS: m/z 152.1 (M+H)⁺

Example 89:N-(5-Cyclopropoxy-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

The title compound was prepared according to Method I by using6-cyclopropoxypyrazin-2-amine instead of 6-ethylpyrazin-2-amine in stepB. ¹H NMR (400 MHz, DMSO-d₆) δ: 10.30 (s, 1H), 7.86 (d, J=7.2 Hz, 1H),7.81 (t, J=7.6 Hz, 1H), 7.42 (t, J=8.4 Hz, 1H), 6.84 (d, J=8.4 Hz, 2H),6.74 (d, J=8.0 Hz, 1H), 4.32-4.45 (m, 1H), 3.56 (s, 6H), 3.37 (q, J=7.2Hz, 2H), 3.09 (s, 3H), 1.01 (t, J=7.2 Hz, 3H), 0.89-0.75 (m, 4H). LC-MS:m/z 527.2 (M+H)⁺

Method J

Step A: N-(3-Bromo-6-chloropyrazin-2-yl)-6-ethoxypicolinamide

A mixture of ethyl 6-ethoxypicolinate (500 mg, 2.60 mmol, 1.0 equiv) and3-bromo-6-chloropyrazin-2-amine (530 mg, 2.60 mmol, 1.0 equiv) intoluene was cooled to 0° C. and AlMe₃ (2.0 mol/L in toluene, 1.95 mL,1.5 equiv) was added dropwise. The reaction mixture was stirred at 100°C. for 16 hours. The mixture was quenched with sat. NH₄Cl solution andextracted with EtOAc (20 mL*3). The combined organic layer was driedover anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash chromatography on silica gel (eluted withPE/EtOAc=10/1) to affordN-(3-bromo-6-chloropyrazin-2-yl)-6-ethoxypicolinamide as a white solid(500 mg, 55% yield). ¹H NMR (400 MHz, DMSO-d₆) δ: 10.94 (s, 1H), 8.50(s, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.68-7.82 (m, 1H), 7.07-7.27 (m, 1H),4.52 (q, J=7.2 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H). LC-MS: m/z 357.7 (M+H)⁺

Step B:N-(6-Chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide

The mixture of N-(3-bromo-6-chloropyrazin-2-yl)-6-ethoxypicolinamide(500 mg, 1.40 mmol, 1.0 equiv), 2,6-dimethoxyaniline (430 mg, 2.80 mmol,2.0 equiv), Xantphos (162 mg, 0.28 mmol, 0.2 equiv), Pd₂(dba)₃ (128 mg,0.140 mmol, 0.1 equiv), potassium t-butoxide (297 mg, 2.80 mmol, 2.0equiv) in toluene (10 mL) was stirred at 110° C. for 16 hours under N₂atmosphere. The mixture was filtered and the filtrate was concentratedin vacuo. The residue was purified by flash column chromatography onsilica gel (eluted with PE/EtOAc=10/1) to affordN-(6-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamideas a light yellow solid (80.0 mg, 13% yield). ¹H NMR (400 MHz,Chloroform-d) δ: 10.11 (s, 1H), 8.40 (s, 1H), 8.02 (s, 1H), 7.92 (d,J=7.2 Hz, 1H), 7.77 (t, J=8.8 Hz, 1H), 7.13 (t, J=8.4 Hz, 1H), 6.97 (d,J=8.0 Hz, 1H), 6.65 (d, J=8.4 Hz, 2H), 4.48 (q, J=7.2 Hz, 2H), 3.82 (s,6H), 1.46-1.52 (m, 3H). LC-MS: m/z 429.7 (M+H)⁺

Step C:5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(ANPA-0002825)

A solution ofN-(6-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide(280 mg, 0.560 mmol, 1.0 equiv) in AcOH (2 mL) was stirred at 120° C.via microwave irradiation for 1 hour. The mixture was concentrated invacuo. The residue was washed with ether, filtered and dried to affordthe title compound5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineas a white solid (200 mg, 75% yield). ¹H NMR (400 MHz, Chloroform-d) δ:8.27 (s, 1H), 8.13-8.20 (m, 1H), 7.69 (t, J=8.4 Hz, 1H), 7.39 (t, J=8.4Hz, 1H), 6.65-6.77 (m, 3H), 3.62 (s, 6H), 3.43 (q, J=7.2 Hz, 2H), 1.09(t, J=7.2 Hz, 3H). LC-MS: m/z 411.7 (M+H)⁺

Step D:N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)morpholine-4-sulfonamide(Example 90)

A suspension of5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(42.0 mg, 0.1 mmol, 1.0 equiv), morpholine-4-sulfonamide (34.0 mg, 0.2mmol, 2.0 equiv), CuI (38.0 mg, 0.2 mmol, 2.0 equiv), trans-N,N′-Dimethylcyclohexane-1, 2-diamine (29.0 mg, 0.2 mmol, 2.0 equiv) andK₂CO₃ (42.0 mg, 0.3 mmol, 3 equiv) in DMF (5 mL) was stirred at 135° C.via microwave irradiation for 6 hours under N₂ atmosphere. The reactionwas quenched with 1N aq. HCOOH solution (30 mL) and extracted with EtOAc(3*60 mL). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated in vacuo. The residue was purified by prep-HPLC (elutedwith CH₃CN/H₂O=5/95-90/10) to obtainN-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)morpholine-4-sulfonamideas a pale yellow solid (17.0 mg, 32% yield). ¹H NMR (400 MHz, DMSO-d₆)δ: 10.91 (s, 1H), 8.12 (s, 1H), 7.99 (d, J=7.2 Hz, 1H), 7.86 (t, J=7.6Hz, 1H), 7.46 (t, J=8.4 Hz, 1H), 6.85 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.4Hz, 1H), 3.62-3.70 (m, 4H), 3.58 (s, 6H), 3.40 (q, J=6.8 Hz, 2H),3.27-3.32 (m, 4H), 1.04 (t, J=6.8 Hz, 3H). LC-MS: m/z 542.0 (M+H)⁺

Example 91:N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)-1-(5-methylpyrimidin-2-yl)methanesulfonamide

The title compound was prepared according to Method J, step D, startingfrom5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using (5-methylpyrimidin-2-yl)methanesulfonamide. ¹H NMR (400 MHz,DMSO-d₆) δ: 11.05 (br. s, 1H), 8.64 (s, 2H), 8.01 (d, J=7.2 Hz, 1H),7.94 (br. s, 1H), 7.87 (t, J=8.0 Hz, 1H), 7.47 (t, J=8.4 Hz, 1H),6.83-6.89 (m, 3H), 5.12 (s, 2H), 3.60 (s, 6H), 3.40 (q, J=7.2 Hz, 2H),2.26 (s, 3H), 1.04 (t, J=6.8 Hz, 3H). LC-MS: m/z 563.3 (M+H)⁺

Example 92:N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)cyclopropanesulfonamide

The title compound was prepared according to Method J, step D, startingfrom5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using cyclopropanesulfonamide. ¹H NMR (400 MHz, Chloroform-d) δ: 8.42(s, 1H), 8.12 (d, J=7.2 Hz, 1H), 7.75 (s, 1H), 7.67 (t, J=8.0 Hz, 1H),7.38 (t, J=8.4 Hz, 1H), 6.68-6.72 (m, 3H), 3.62 (s, 6H), 3.44 (q, J=8.0Hz, 2H), 2.93-2.98 (m, 1H), 1.28-1.32 (m, 2H), 1.04-1.11 (m, 5H). LC-MS:m/z 497.2 (M+H)⁺

Step A: tert-Butyl3-((N-(2,4-dimethoxybenzyl)sulfamoylmethyl)-3-hydroxyazetidine-1-carboxylate

To a solution of N-(2,4-dimethoxybenzyl)-methanesulfonamide (500 mg,2.04 mmol, 1.0 equiv) in THF (4 mL) at −70° C. under N₂ was added n-BuLi(2.5 mL, 2.5 mol/L in THF, 6.25 mmol, 3.1 equiv) dropwise. The reactionmixture was stirred at −70° C. for 1 hour, and then tert-butyl3-oxoazetidine-1-carboxylate (699 mg, 4.08 mmol, 2.0 equiv) dissolved inTHF (4 mL) was added dropwise. After 1 hour at −70° C., the reactionmixture was allowed slowly to warm up to room temperature and stirredovernight. The reaction was quenched with 5 mL MeOH, concentrated invacuo and purified by column chromatography on silica gel (eluted withEtOAc/PE=2/3) to afford tert-butyl3-((N-(2,4-dimethoxybenzyl)sulfamoyl)methyl)-3-hydroxyazetidine-1-carboxylateas a pale yellow solid (520 mg, 61% yield). LC-MS: m/z 417.1 (M+H)⁺

Step B: (3-Hydroxyazetidin-3-yl)methanesulfonamide

To a solution of tert-butyl3-((N-(2,4-dimethoxybenzyl)sulfamoyl)methyl)-3-hydroxyazetidine-1-carboxylate(470 mg, 1.10 mmol, 1.0 equiv) in DCM (10 mL) was addedtrifluoroethanoic acid (0.5 mL). The reaction mixture was stirred atroom temperature overnight. It was filtered and the filter cakeredissolved in methanol, filtered and the filtrated was concentratedunder vacuum to give (3-hydroxyazetidin-3-yl)methanesulfonamide TFA saltas a white solid (100 mg, 54% yield). LC-MS: m/z 167.0 (M+H)⁺

Step C: (3-Hydroxy-1-methylazetidin-3-yl)methanesulfonamide

To a solution of (3-hydroxyazetidin-3-yl)methanesulfonamide (100 mg,0.600 mmol, 1.0 equiv) in methanol (10 mL) were added triethylamine (242mg, 2.40 mmol, 4.0 equiv) and di-tert-butyl dicarbonate (137 mg, 0.630mmol, 1.05 equiv) at 0° C. The mixture was stirred at 40° C. overnight.The reaction mixture was concentrated under vacuum and the residue waspurified by flash chromatography (eluted with DCM/MeOH=40/1) to give(3-hydroxy-1-methylazetidin-3-yl)methanesulfonamide as a white solid(80.0 mg, 47% yield). LC-MS: m/z 267.1 (M+H)⁺

Step D: tert-Butyl3-((N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)sulfamoyl)methyl)-3-hydroxyazetidine-1-carboxylate

A solution of (3-hydroxy-1-methylazetidin-3-yl)methanesulfonamide (80.0mg, 0.300 mmol, 1.0 equiv),5-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(273 mg, 0.600 mmol, 2.0 equiv), CuI (114 mg, 0.600 mmol, 2.0 equiv),trans-N, N′-Dimethylcyclohexane-1, 2-diamine (85.3 mg, 0.600 mmol, 2.0equiv) and K₂CO₃ (124 mg, 0.900 mmol, 3.0 equiv) in DMF (2 mL) wasstirred at 110° C. via microwave irradiation for 2 hours under N₂atmosphere. The mixture was diluted with DCM (20 mL), acidified withformic acid (2 mL), and extracted with DCM (20 mL*2). The organic phasewas concentrated in vacuo and the residue was purified by flashchromatography (eluted with DCM/MeOH=40/1) to afford tert-butyl3-((N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)sulfamoyl)methyl)-3-hydroxyazetidine-1-carboxylateas a pale yellow solid. (70.0 mg, 36% yield). LC-MS: m/z 642.1 (M+H)⁺

Step E:N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)-1-(3-hydroxyazetidine-3-yl)methanesulfonamide(Example 93)

A solution of tert-butyl3-((N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)sulfamoyl)methyl)-3-hydroxyazetidine-1-carboxylate(70.0 mg, 0.109 mmol) in AcOH (5 mL) was stirred at room temperatureovernight. The reaction mixture was adjusted to pH=7-8 with ammoniumhydroxide and concentrated under vacuum. The residue was purified byprep-HPLC to giveN-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)-1-(3-hydroxyazetidin-3-yl)methanesulfonamideas a yellow solid (20.0 mg, 34% yield). ¹H NMR (400 MHz, DMSO-d₆) δ:7.89 (d, J=7.2 Hz, 1H), 7.80 (t, J=7.6 Hz, 1H), 7.59 (s, 1H), 7.41 (t,J=8.4 Hz, 1H), 6.82 (d, J=8.4 Hz, 2H), 6.74 (d, J=8.0 Hz, 1H), 4.31 (d,J=11.2 Hz, 2H), 3.79 (d, J=11.2 Hz, 2H), 3.61 (s, 2H), 3.57 (s, 6H),3.37 (d, J=7.2 Hz, 3H), 1.02 (t, J=7.2 Hz, 3H). LC-MS: m/z 542.1 (M+H)⁺

Method K

Step A: N-(3,5-Dibromo-6-chloropyrazin-2-yl)-6-ethoxypicolinamide

To a solution of 3,5-dibromo-6-chloropyrazin-2-amine (2.00 g, 6.97 mmol,1.0 equiv) in anhydrous toluene (50 mL) was added Al(Me)₃ (2 mol/L intoluene, 5.20 mL, 10.4 mmol, 1.5 equiv) dropwise at 0° C. under N₂atmosphere. After the mixture was stirred at 0° C. for 30 minutes and at50° C. for 30 minutes, ethyl 6-ethoxypicolinate (1.36 g, 6.97 mmol, 1.0equiv) was added. The mixture was stirred at 50° C. for 3 hours. Thereaction mixture was quenched with 1N HCl solution (100 mL), followed byextraction with DCM (50 mL*2). The combined organic layers were driedover anhydrous Na₂SO₄ and concentrated in vacuo. The residue wasreslurried in MeOH (50 mL). The mixture was filtered to afford the titlecompound N-(3,5-dibromo-6-chloropyrazin-2-yl)-6-ethoxypicolinamide as ayellow solid (2.30 g, 76% yield). LC-MS: m/z 434.9, 436.9, 438.9 (M+H)⁺

Step B:N-(5-Bromo-6-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide

A suspension ofN-(3,5-dibromo-6-chloropyrazin-2-yl)-6-ethoxypicolinamide (1.00 g, 2.30mmol, 1.0 equiv), 2,6-dimethoxyaniline (351 mg, 2.30 mmol, 1.0 equiv),Pd₂(dba)₃ (420 mg, 0.460 mmol, 0.2 equiv), Xantphos (530 mg, 0.520 mmol,0.4 equiv) and K₂CO₃ (632 mg, 4.60 mmol, 3.0 equiv) in 1,4-dioxane (15mL) was stirred at 100° C. via microwave irradiation for 2 hours underN₂ atmosphere. The mixture was filtered and the filtrate wasconcentrated to dryness. The residue was purified by silica gel columnchromatography (eluted with PE/EtOAc=10/1˜5/1) to affordN-(5-bromo-6-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamideas a yellow solid (480 mg, 41% yield). LC-MS: m/z 508.0, 510.0 (M+H)⁺

Step C:6-Bromo-5-chloro-1-(2,6-dimethoxyphenyl-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine

The solution ofN-(5-bromo-6-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamideamide (400 mg, 0.780 mmol, 1.0 equiv) in AcOH (10 mL) was stirred at110° C. via microwave irradiation for 4 hours. The mixture was cooled toroom temperature and the precipitate was filtered off to afford thetitle compound6-bromo-5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineas a yellow solid (220 mg, 57% yield). LC-MS: m/z 490.0, 492.0 (M+H)⁺

Step D:N-(5-Chloro-1-(2,6-dimethoxyphenyl-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide(Example 64)

A suspension of6-Bromo-5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(200 mg, 0.410 mmol, 1.0 equiv), methanesulfonamide (38.0 mg, 0.410mmol, 1.0 equiv), CuI (155 mg, 0.820 mmol, 2.0 equiv), trans-N,N′-Dimethylcyclohexane-1, 2-diamine (116 mg, 0.820 mmol, 2.0 equiv) andK₂CO₃ (168 mg, 1.23 mmol, 3.0 equiv) in DMF (10 mL) was stirred at 100°C. for 2 hours under N₂ atmosphere. The mixture was diluted with 1N HClsolution (20 mL) and extracted with EtOAc (2*50 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by flash chromatography to affordN-(5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamideas yellow solid (120 mg, 59% yield). ¹H NMR (400 MHz, DMSO-d₆) δ: 10.69(br. s, 1H), 7.94 (d, J=7.2 Hz, 1H), 7.87 (t, J=8.0 Hz, 1H), 7.46 (t,J=8.4 Hz, 1H), 6.83-6.87 (m, 3H), 3.57 (s, 6H), 3.39 (q, J=7.2 Hz, 2H),3.12 (s, 3H), 1.02 (t, J=7.2 Hz, 3H). LC-MS: m/z 505.0 (M+H)⁺

Step A: 2-(Chloromethyl)-3-fluoropyridine

To a solution of (3-fluoropyridin-2-yl)methanol (1.80 g, 13.8 mmol, 1.0equiv) in DCM (20 mL) was added SOCl₂ (2.50 mL, 35.0 mmol, 2.5 equiv)dropwise at 0° C. The resulting mixture was stirred at room temperaturefor 2 hours. The reaction mixture was quenched with saturated aqueousNaHCO₃ solution and extracted with DCM (3*20 mL). The combined organiclayers were dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by column chromatography (eluted with PE/EtOAc=5/1)to afford 2-(chloromethyl)-3-fluoropyridine (1.33 g, 66% yield). LC-MS:m/z 146.0, 148.0 (M+H)⁺

Step B: S-((3-Fluoropyridin-2-yl)methyl) ethanethioate

To a solution of 2-(chloromethyl)-3-fluoropyridine (1.00 g, 6.70 mmol,1.0 equiv) in acetone (20 mL) was added potassium ethanethioate (918 mg,8.00 mmol, 1.2 equiv) in one portion. The resulting mixture was refluxedovernight. The reaction mixture was filtered through a short silica gelcolumn. The filtrate was concentrated in vacuo and the residue waspurified by column chromatography (eluted with PE/EtOAc=5/1) to affordS-((3-fluoropyridin-2-yl)methyl) ethanethioate (1.00 g, 81% yield).LC-MS: m/z 186.0 (M+H)⁺

Step C: (3-Fluoropyridin-2-yl)methanesulfonamide

Sodium hypochlorite (9% aq. solution) (12.0 mL, 16.2 mmol, 6.0 equiv)was added dropwise to a vigorous stirring solution ofS-((3-fluoropyridin-2-yl)methyl) ethanethioate (500 mg, 2.70 mmol, 1.0equiv) in DCM (17 mL) and 1 N HCl solution (16.2 mL, 16.2 mmol, 6.0equiv) at −20° C. After the completion of addition, the mixture wasstirred at -20° C. for 1 hour. Then NH₃ (gas) was bubbled into themixture at −20° C. for 10 minutes. The mixture was allowed to slowlywarm up to room temperature and stirred for 1 hour. The mixture wasconcentrated under vacuum. The residue was purified by silica gelchromatography (eluted with DCM/MeOH=25/1) to afford(3-fluoropyridin-2-yl)methanesulfonamide as a white solid (250 mg, 49%yield). LC-MS: m/z 191.0 (M+H)⁺

Example 94:N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(3-fluoropyridin-2-yl)methanesulfonamide

The title compound was prepared according to Method K, step D, startingfrom6-bromo-5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using (3-fluoropyridin-2-yl)methanesulfonamide. ¹H NMR (400 MHz,DMSO-d₆) δ: 10.97 (s, 1H), 8.39 (d, J=4.0 Hz, 1H), 7.97 (d, J=8.0 Hz,1H), 7.89 (t, J=8.0 Hz, 1H), 7.70-7.75 (m, 1H), 7.43-7.50 (m, 2H),6.84-6.87 (m, 3H), 4.89 (s, 2H), 3.56 (s, 6H), 3.40 (q, J=8.0 Hz, 2H),1.02 (t, J=8.0 Hz, 3H). LC-MS: m/z 600.1 (M+H)⁺

Pyridin-2-yl methanesulfonamide

Pyridin-2-ylmethanesulfonamide was prepared according to the preparationof (3-Fluoropyridin-2-yl)methanesulfonamide by using2-(chloromethyl)pyridine at step A. LC-MS: m/z 173.0 (M+H)⁺

Example 95:N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(pyridin-2-yl)methanesulfonamide

The title compound was prepared according to Method K, step D, startingfrom6-Bromo-5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using pyridin-2-ylmethanesulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ:8.51 (d, J=4.0 Hz, 1H), 7.94 (d, J=7.2 Hz, 1H), 7.86 (t, J=8.0 Hz, 1H),7.76-7.72 (m, 1H), 7.46 (t, J=8.8 Hz, 1H), 7.34-7.30 (m, 1H), 7.08 (d,J=7.6 Hz, 1H), 6.82-6.87 (m, 3H), 4.71 (s, 2H), 3.55 (s, 6H), 3.39 (q,J=7.2 Hz, 2H), 1.01 (t, J=7.2 Hz, 3H). LC-MS: m/z 582.1 (M+H)⁺

(5-Fluoropyridin-2-yl)methanesulfonamide

(5-Fluoropyridin-2-yl)methanesulfonamide was prepared according to thepreparation of (3-Fluoropyridin-2-yl)methanesulfonamide by using(5-fluoropyridin-2-yl)methanol at step A. LC-MS: m/z 191.0 (M+H)⁺

Example 96:N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(5-fluoropyridin-2-yl)methanesulfonamide

The title compound was prepared according to Method K, step D, startingfrom6-Bromo-5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using (3-fluoropyridin-2-yl)methanesulfonamide. ¹H NMR (400 MHz,DMSO-d₆) δ: 10.91 (s, 1H), 8.53 (d, J=2.4 Hz, 1H), 7.98 (d, J=8.0 Hz,1H), 7.88 (t, J=8.0 Hz, 1H), 7.70-7.75 (m, 1H), 7.48 (d, J=8.0 Hz, 1H),7.19 (dd, J=12.0, 4.0 Hz, 1H), 6.85-6.89 (m, 3H), 4.79 (s, 2H), 3.57 (s,6H), 3.40 (q, J=8.0 Hz, 2H), 1.02 (t, J=8.0 Hz, 3H). LC-MS: m/z 600.1(M+H)⁺

Example 97:N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)cyclopropanesulfonamide

The title compound was prepared according to Method K, step D, startingfrom6-Bromo-5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using cyclopropanesulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ: 10.66 (s,1H), 7.96 (d, J=7.6 Hz, 1H), 7.87 (t, J=7.6 Hz, 1H), 7.48 (t, J=8.4 Hz,1H), 6.85-6.89 (m, 3H), 3.57 (s, 6H), 3.39 (q, J=7.2 Hz, 2H), 2.71-2.76(m, 1H), 1.02 (t, J=7.2 Hz, 3H), 0.91-0.95 (m, 2H), 0.81-0.85 (m, 2H).LC-MS: m/z 531.1 (M+H)⁺

Morpholine-4-sulfonamide

The title compound was prepared according to the preparation ofpyrrolidine-1-sulfonamide by using morpholine. ¹H NMR (400 MHz, DMSO-d₆)δ: 6.82 (s, 2H), 3.61-3.68 (m, 4H), 2.89-2.94 (m, 4H).

Example 98:N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)morpholine-4-sulfonamide

The title compound was prepared according to Method K, step D, startingfrom6-Bromo-5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using morpholine-4-sulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ: 10.60(s, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.87 (t, J=7.6 Hz, 1H), 7.47 (t, J=8.4Hz, 1H), 6.48-6.89 (m, 3H), 3.60 (s, 6H), 3.35-3.42 (m, 6H), 2.90 (t,J=4.4 Hz, 4H), 1.02 (t, J=6.8 Hz, 3H). LC-MS: m/z 576.1, 578.2 (M+H)⁺

Step A: 5-Fluoropyridine-2-thiol

A solution of 2-bromo-5-fluoropyridine (3.00 g, 17.0 mmol, 1.0 equiv) inanhydrous toluene (2 mL) was added dropwise into a solution of n-BuLi(7.48 mL, 2.5 mol/L in hexane, 18.7 mmol, 1.1 equiv) in anhydroustoluene (38 mL) at −78° C. The reaction mixture was stirred for 5minutes at −78° C. Sulfur power (0.550 g, 17.0 mmol, 1.0 equiv) wasadded to the solution and then resulting mixture was warmed up to roomtemperature and stirred for additional 1 hour. The reaction mixture wasquenched with H₂O (1 mL) and adjusted pH to 3.0 with HCl (1 N). Theresulting mixture was extracted with DCM (25 mL*3). The combined organicphase was washed with brine (30 mL), dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was purified by flashchromatography on silica gel (eluted with PE/EtOAc=2/1) to afford thetitle compound 5-fluoropyridine-2-thiol as a yellow solid (700 mg, 32%yield). LC-MS: m/z 130.0 (M+H)⁺

Step B: 5-Fluoropyridine-2-sulfonyl chloride

Sodium hypochlorite (9% aq. solution)(10 mL, 20.1 mmol, 3.7 equiv) wasadded dropwise to a rapidly stirring solution of5-fluoropyridine-2-thiol (0.700 g, 5.40 mmol, 1.0 equiv) in DCM (20 mL)and 1N HCl solution (20.1 mL, 20.1 mmol, 3.7 equiv) at 0° C. After theaddition was completed, the mixture was stirred at 0° C. for 30 minutes.The organic layer was separated and used directly for the next step.

Step C: 5-Fluoropyridine-2-sulfonamide

The solution of 5-fluoropyridine-2-sulfonyl chloride in DCM (20 mL) wasadded to NH₄OH (aq., 34%, 15 mL) at 0° C. and the mixture was allowed towarm up to room temperature slowly and stirred for 1 hour. The mixturewas concentrated under vacuum and the residue was purified by silica gelchromatography (eluted with PE/EtOAc=1/1) to afford5-fluoropyridine-2-sulfonamide as an orange solid (170 mg, 18% yield intwo steps). LC-MS: m/z 177.0 (M+H)⁺

Example 99:N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-5-fluoropyridine-2-sulfonamide

The title compound was prepared according to Method K, step D, startingfrom6-bromo-5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using 5-fluoropyridine-2-sulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ:8.57 (d, J=2.4 Hz, 1H), 7.93 (d, J=7.2 Hz, 1H), 7.83 (t, J=8.0 Hz, 1H),7.45-7.58 (m, 3H), 6.84 (dd, J=10.0, 8.4 Hz, 3H), 3.51 (s, 6H), 3.33 (q,J=7.2 Hz, 3H), 1.01 (t, J=7.2 Hz, 3H). LC-MS: m/z 586.1 (M+H)⁺

Example 100:N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(2-fluoro-4-methylphenyl)methanesulfonamide

The title compound was prepared according to Method K, step D, startingfrom6-bromo-5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using (2-fluoro-4-methylphenyl)methanesulfonamide. ¹H NMR (400 MHz,DMSO-d₆) δ: 10.92 (s, 1H), 7.99 (dd, J=7.2, 0.4 Hz, 1H), 7.89 (t, J=7.6Hz, 1H), 7.48 (t, J=8.4 Hz, 1H), 7.04 (d, J=11.2 Hz, 1H), 6.97-7.00 (m,2H), 6.88 (d, J=8.4, 2H), 6.87 (dd, J=8.0, 0.4 Hz, 1H), 4.64 (s, 2H),3.57 (s, 6H), 3.40 (d, J=7.2 Hz, 2H), 2.31 (s, 3H), 1.02 (t, J=7.2 Hz,3H). LC-MS: m/z 613.1 (M+H)⁺

Example 101:N-(5-Chloro-1-(2,6-dmethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-5-methylpyridine-2-sulfonamide

The title compound was prepared according to Method K, step D, startingfrom6-bromo-5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using 5-methylpyridine-2-sulfonamide. ¹HNMR (400 MHz, DMSO-d₆) δ:11.60 (br. s, 1H), 8.38 (s, 1H), 7.92 (d, J=7.2 Hz, 1H), 7.83 (d, J=7.6Hz, 1H), 7.56 (t, J=8.4 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0Hz, 1H), 6.88 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.0 Hz, 1H), 3.50 (s, 6H),3.34 (q, J=7.2 Hz, 2H), 2.35 (s, 3H), 1.01 (t, J=7.2 Hz, 3H). LC-MS: m/z582.1 (M+H)⁺

Example 102:N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)pyridine-2-sulfonamide

The title compound was prepared according to Method K, step D, startingfrom6-bromo-5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using pyridine-2-sulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ: 11.66 (s,1H), 8.36-8.61 (m, 1H), 7.87 (d, J=7.2 Hz, 1H), 7.80 (t, J=7.6 Hz, 1H),7.52 (t, J=8.4 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H),6.77 (d, J=8.0 Hz, 1H), 3.50 (s, 6H), 3.33 (q, J=7.2 Hz, 2H), 1.00 (t,J=7.2 Hz, 3H). LC-MS: m/z 568.1 (M+H)⁺

Step A: 4-(Fluoromethyl)benzenesulfonamide

A mixture of 4-methylbenzenesulfonamide (1.71 g, 10.0 mmol, 1.0 equiv),AgNO₃ (340 mg, 2.00 mmol, 0.2 equiv), Na₂S₂O₈ (11.9 g, 50.0 mmol, 5equiv) and Selectfluor (14.2 g, 40.0 mmol, 4 equiv) in CH₃CN (75 mL) andH₂O (75 mL) was stirred at 80° C. for 5 hours under N₂. The resultingmixture was extracted with DCM (3*50 mL). The combined organic phase waswashed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash chromatography on silicagel (eluted with DCM/Et₃N=100/1) to afford the title compound4-(fluoromethyl)benzenesulfonamide as a yellow solid (0.61 g, 84%purity, 27% yield). ¹H NMR (400 MHz, DMSO-d₆) δ: 7.91-7.83 (m, 2H),7.63-7.55 (m, 2H), 7.40 (s, 2H), 5.52 (d, J=47.2 Hz, 2H). LC-MS: m/z190.0 (M+H)⁺

Example 103:N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-4-(fluoromethyl)benzenesulfonamide

The title compound was prepared according to Method K, step D, startingfrom6-bromo-5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using 4-(fluoromethyl)benzenesulfonamide. ¹H NMR (400 MHz, DMSO-d₆)δ: 11.25 (s, 1H), 7.92 (d, J=7.2 Hz, 1H), 7.83 (t, J=8.0 Hz, 1H),7.68-7.52 (m, 3H), 7.27 (d, J=8.0 Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 6.82(d, J=8.4 Hz, 1H), 5.47 (d, J=48.0 Hz, 2H), 3.54 (s, 6H), 3.38 (q, J=7.2Hz, 2H), 1.03 (t, J=7.2 Hz, 3H). LC-MS: m/z 599.1 (M+H)⁺

Example 104:N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)pyridine-3-sulfonamide

The title compound was prepared according to Method K, step D, startingfrom6-bromo-5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using pyridine-3-sulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.76-8.84(m, 1H), 8.64-8.75 (m, 1H), 7.94 (d, J=7.2 Hz, 1H), 7.85 (t, J=7.6 Hz,1H), 7.79 (dt, J=8.0, 2.0 Hz, 1H), 7.60 (t, J=8.4 Hz, 1H), 7.21-7.33 (m,1H), 6.96 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.0 Hz, 1H), 3.56 (s, 6H), 3.38(q, J=7.2 Hz, 2H), 1.03 (t, J=7.2 Hz, 3H). LC-MS: m/z 568.2 (M+H)⁺

Example 105:N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(5-fluoropyrimidin-2-yl)methanesulfonamide

The title compound was prepared according to Method K, step D, startingfrom6-bromo-5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using (5-fluoropyrimidin-2-yl)methanesulfonamide. ¹H NMR (400 MHz,Chloroform-d) δ: 8.55 (s, 2H), 8.06 (d, J=7.2 Hz, 1H), 7.68 (t, J=7.6Hz, 1H), 7.42 (s, 1H), 7.38 (t, J=8.4 Hz, 1H), 6.70 (d, J=8.0 Hz, 1H),6.67 (d, J=8.4 Hz, 2H), 4.99 (s, 2H), 3.59 (s, 6H), 3.42 (q, J=7.2 Hz,2H), 1.06 (t, J=7.2 Hz, 3H). LC-MS: m/z 601.1 (M+H)⁺

Step A: 4-(Hydroxymethyl)benzenesulfonamide

To a solution of 4-sulfamoylbenzoic acid (5.00 g, 25.0 mmol, 1.0 equiv)in THF (250 mL) was added B₂H₆ (100 mL, 1 mol/L in THF, 100 mmol, 4equiv) dropwise at 0° C. The mixture was stirred for 0.5 hour at 0° C.The mixture was allowed to warm to room temperature slowly and stirredfor another 18 hours. Then the mixture was cooled to 0° C. and the 50 mLMeOH was added dropwise. After refluxed for 1 h, 2 mol/L HCl (50 mL) wasadded to the solution and the reaction mixture was refluxed for another30 mins. The mixture was concentrated under vacuum and the residue waspurified by silica gel chromatography (eluted with DCM/MeOH=100/8) toafford 4-(hydroxymethyl)benzenesulfonamide as a white solid (3.12 g, 67%yield). ¹H NMR (400 MHz, DMSO-d₆) δ: 7.77 (d, J=8.4 Hz, 2H), 7.48 (d,J=8.4 Hz, 2H), 7.29 (s, 2H), 5.37 (t, J=5.6 Hz, 1H), 4.57 (d, J=5.6 Hz,2H). LC-MS: m/z 188.0 (M+H)⁺

Step B: 4-Formylbenzenesulfonamide

A mixture of 4-(hydroxymethyl)benzenesulfonamide (1.00 g, 5.35 mmol, 1.0equiv) and Dess-Martin periodinane (3.40 g, 8.02 mmol, 1.5 equiv) inCH₃CN (40 mL) was stirred at 80° C. for 2 hours. Then aq. NaHCO₃solution and aq. Na₂S₂O₃ solution were added. The mixture was filteredand the filtrate was concentrated. The residue was purified by flashchromatography on silica gel (eluted with PE/EtOAc=1/1) to afford4-formylbenzenesulfonamide as a white solid (820 mg, 83% yield). ¹H NMR(400 MHz, DMSO-d₆) δ: 10.10 (s, 1H), 8.10 (d, J=8.4 Hz, 2H), 8.03 (d,J=8.4 Hz, 2H), 7.60 (s, 2H). LC-MS: m/z 186.0 (M+H)⁺

Step C:N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-4-formylbenzenesulfonamide

N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-4-formylbenzenesulfonamidewas prepared according to Method K, step D, by using4-formylbenzenesulfonamide. LC-MS: m/z 595.1 (M+H)⁺

Example 106:N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-4-(difluoromethyl)benzenesulfonamide

DAST (5.60*10⁻⁶ L, 0.042 mmol, 2.5 equiv) was added to a stirredsolution ofN-(5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-4-formylbenzenesulfonamide(10.0 mg, 0.017 mmol, 1.0 equiv) in DCM (1 mL) at −78° C. Then thecooling bath was removed. The reaction mixture was warmed up to roomtemperature and stirred for 1.5 hours. Additional portion of DAST(5.60*10⁻⁶ L, 0.042 mmol, 2.5 equiv) was added. The resulting mixturewas stirred at room temperature overnight. The mixture was concentratedunder vacuum and the residue was purified by prep-HPLC (eluted witheluted with CH₃CN/H₂O=5/95˜95/5) to affordN-(5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-4-(difluoromethyl)benzenesulfonamideas a yellow solid (2.5 mg, 24% yield). ¹H NMR (400 MHz, DMSO-d₆) δ:11.40 (s, 1H), 7.93 (d, J=7.2 Hz, 1H), 7.84 (t, J=7.6 Hz, 1H), 7.73-7.53(m, 3H), 7.45 (d, J=8.0 Hz, 2H), 7.10 (t, J=55.2 Hz, 1H), 6.97 (d, J=8.4Hz, 2H), 6.83 (d, J=8.0 Hz, 1H), 3.53 (s, 6H), 3.40 (q, J=7.2 Hz, 2H),1.03 (t, J=7.2 Hz, 3H). LC-MS: m/z 617.1 (M+H)⁺

Example 107:N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(3-fluoro-4-methylphenyl)methanesulfonamide

The title compound was prepared according to Method K, step D, startingfrom6-bromo-5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using (3-fluoro-4-methylphenyl)methanesulfonamide. ¹H NMR (400 MHz,DMSO-d₆) δ: 8.00 (d, J=7.2 Hz, 1H), 7.92-7.86 (m, 1H), 7.49 (t, J=8.4Hz, 1H), 7.23 (t, J=8.0 Hz, 1H), 7.04-6.67 (m, 5H), 4.58 (s, 2H), 3.59(s, 6H), 3.39 (q, J=7.2 Hz, 2H), 2.21 (s, 3H), 1.07 (t, J=7.2 Hz, 3H).LC-MS: m/z 613.1 (M+H)⁺

Example 108:N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(4-fluorophenyl)methanesulfonamide

The title compound was prepared according to Method K, step D, startingfrom6-bromo-5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using (4-fluorophenyl)methanesulfonamide. ¹H NMR (400 MHz,Chloroform-d) δ: 8.12 (d, J=6.8 Hz, 1H), 7.70 (t, J=8.0 Hz 1H), 7.42 (t,J=8.4 Hz, 1H), 7.17 (s, 1H), 7.08-7.15 (m, 2H), 6.96-7.03 (m, 2H),6.67-6.76 (m, 3H), 4.61 (s, 2H), 3.63 (s, 6H), 3.43 (q, J=7.2 Hz, 2H),1.08 (t, J=7.2 Hz, 3H). LC-MS: m/z 599.1 (M+H)⁺

Example 109:N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(pyrimidin-2-yl)methanesulfonamide

The title compound was prepared according to Method K, step D, startingfrom6-bromo-5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using pyrimidin-2-ylmethanesulfonamide. ¹H NMR (400 MHz,Chloroform-d) δ: 8.70 (d, J=4.8 Hz, 2H), 8.06 (dd, J=7.6, 0.8 Hz, 1H),7.68 (td, J=7.6, 0.8 Hz, 1H), 7.51 (s, 1H), 7.36 (t, J=8.4 Hz, 1H),7.25-7.26 (m, 1H), 6.70 (dd, J=8.4, 0.8 Hz, 1H), 6.67 (d, J=8.4 Hz, 2H),4.99 (s, 2H), 3.59 (s, 6H), 3.43 (q, J=7.2 Hz, 2H), 1.06 (t, J=7.2 Hz,3H). LC-MS: m/z 583.1 (M+H)⁺

Example 110:N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)but-2-yne-1-sulfonamide

The title compound was prepared according to Method K, step D, startingfrom6-bromo-5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using but-2-yne-1-sulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ: 11.20(br. s, 1H), 7.96 (dd, J=7.2, 0.8 Hz, 1H), 7.88 (t, J=8.0 Hz, 1H), 7.48(t, J=8.4 Hz, 1H), 6.84-6.90 (m, 3H), 4.30 (d, J=2.0 Hz, 2H), 3.58 (s,6H), 3.41 (d, J=7.2 Hz, 2H), 1.79 (t, J=2.0 Hz, 3H), 1.02 (t, J=7.2 Hz,3H). LC-MS: m/z 543.2 (M+H)⁺

Example 111:N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)tetrahydro-2H-pyran-4-sulfonamide

The title compound was prepared according to Method K, step D, startingfrom6-bromo-5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using tetrahydro-2H-pyran-4-sulfonamide. ¹H NMR (400 MHz,Chloroform-d) δ: 8.11 (d, J=7.2 Hz, 1H), 7.69 (t, J=8.0 Hz, 1H), 7.39(t, J=8.4 Hz, 1H), 7.29 (s, 1H), 6.66-6.76 (m, 3H), 3.95-4.04 (m, 2H),3.74-3.86 (m, 1H), 3.63 (s, 6H), 3.42 (q, J=7.2 Hz, 2H), 3.04 (td,J=11.2, 3.2 Hz, 2H), 1.81-1.98 (m, 4H), 1.07 (t, J=7.2 Hz, 3H). LC-MS:m/z 575.1 (M+H)⁺

Example 112:N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-N′-methyl-N′-cyclopropylsulfamide

The title compound was prepared according to Method K, step D, startingfrom6-bromo-5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using N-methyl-N-cyclopropylsulfamide. ¹H NMR (400 MHz, DMSO-d₆)δ:10.56 (s, 1H), 7.98 (d, J=7.2 Hz, 1H), 7.86 (t, J=8.0 Hz, 1H), 7.43(t, J=8.4 Hz, 1H), 6.85 (d, J=8.4 Hz, 2H and 1H), 3.59 (s, 6H), 3.36 (q,J=7.2 Hz, 2H), 2.52 (s, 3H), 2.24-2.31 (m, 1H), 1.02 (t, J=7.2 Hz, 3H),0.48-0.58 (m, 2H), 0.30-0.40 (m, 2H). LC-MS: m/z 560.2 (M+H)⁺

N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropylmethanesulfonamide

N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)methanesulfonamidedimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine byusing (1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)methanesulfonamide.LC-MS: m/z 645.2 (M+H)⁺

Example 113:N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(1-hydroxycyclopropyl)methanesulfonamide

The title compound was prepared according to step I of synthesis ofExample 81. ¹H NMR (400 MHz, DMSO-d₆) δ:10.47 (br. s, 1H), 7.93 (d,J=7.2 Hz, 1H), 7.85 (t, J=7.6 Hz, 1H), 7.45 (t, J=8.4 Hz, 1H), 6.81-6.86(m, 3H), 5.32 (br. s, 1H), 3.57 (s, 6H), 3.46 (s, 2H), 3.37 (q, J=7.2Hz, 2H), 1.01 (t, J=7.2 Hz, 3H), 0.59 (t, J=4.8 Hz, 2H), 0.33-0.36 (m,2H). LC-MS: m/z 561.0 (M+H)⁺

Example 114:N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(5-methylpyridin-2-yl)methanesulfonamide

The title compound was prepared according to Method K, step D, startingfrom6-bromo-5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using (5-methylpyrimidin-2-yl)methanesulfonamide. ¹H NMR (400 MHz,DMSO-d₆) δ: 10.86 (s, 1H), 8.63 (s, 2H), 7.96 (d, J=6.8 Hz, 1H), 7.88(t, J=7.6 Hz, 1H), 7.44 (t, J=8.4 Hz, 1H), 6.78-6.90 (m, 3H), 4.87 (s,2H), 3.51 (s, 6H), 3.39 (q, J=7.2 Hz, 2H), 2.26 (s, 3H), 1.01 (t, J=7.2Hz, 3H). LC-MS: m/z 597.1 (M+H)⁺

Example 115:N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)methanesulfonamide

The title compound was prepared according to Example 81 using6-bromo-5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazinein step H. ¹H NMR (400 MHz, Chloroform-d) δ: 8.09 (dd, J=7.2, 0.8 Hz,1H), 7.68 (t, J=7.6 Hz, 1H), 7.39 (t, J=8.4 Hz, 1H), 7.31 (s, 1H),6.69-6.72 (m, 3H), 3.63 (s, 6H), 3.54 (d, J=7.2 Hz, 2H), 3.42 (q, J=7.2Hz, 2H), 2.22-2.33 (m, 3H), 1.65-1.71 (m, 2H), 1.35 (s, 3H), 1.07 (t,J=7.2 Hz, 3H). LC-MS: m/z 589.1 (M+H)⁺

Example 116:N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-4-hydroxypiperidine-1-sulfonamide

The title compound was prepared according to Method K, step D, startingfrom6-bromo-5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using 4-hydroxypiperidine-1-sulfonamide. ¹H NMR (400 MHz,Chloroform-d) δ: 8.13 (d, J=7.2 Hz, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.49(s, 1H), 7.37 (t, J=8.4 Hz, 1H), 6.70 (d, J=7.6 Hz, 1H), 6.67 (d, J=8.4Hz, 2H), 3.60-3.64 (m, 7H), 3.40 (q, J=7.2 Hz, 2H), 3.28-3.36 (m, 2H),2.80-2.90 (m, 2H), 1.68-1.71 (m, 2H), 1.39-1.48 (m, 2H), 1.07 (t, J=7.2Hz, 3H). LC-MS: m/z 589.9 (M+H)⁺

Step A: 3,5-Dimethoxyisonicotinonitrile

To a solution of 3,5-dichloroisonicotinonitrile (10.0 g, 57.8 mmol, 1.0equiv) in MeOH (100 mL) was added MeONa (43.0 mL, 5.4 mol/L in MeOH, 231mmol, 4.0 equiv). The mixture was refluxed for 4 hours. The reaction wasquenched by added H₂O (5 mL), and concentrated under vacuum. The residuewas washed by H₂O, dried under vacuum to afford the title compound3,5-dimethoxyisonicotinonitrile as a white solid (8.88 g, 94% yield).LC-MS: m/z 165.1 (M+H)⁺

Step B: 3,5-Dimethoxyisonicotinic acid

A solution of 3,5-dimethoxyisonicotinonitrile (8.88 g, 54.1 mmol, 1.0equiv) in H₂SO₄ (8 mol/L in H₂O, 120 mL) was stirred at 120° C. for 6hours. The resulting mixture was used directly for next step. LC-MS: m/z184.1 (M+H)⁺

Step C: Methyl 3,5-dimethoxyisonicotinate

MeOH (50 mL) was added into a solution of step B. The mixture wasrefluxed overnight. The pH of the mixture was adjusted to 8 using 1 Naq. NaOH solution. The resulting mixture was extracted with EtOAc (3*100mL). The combined organic phase was washed with brine (100 mL), driedover anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by flash chromatography on silica gel (eluted withPE/EtOAc=1/1) to afford methyl 3,5-dimethoxyisonicotinate as a whitesolid (5.50 g, 52% yield in two steps). ¹H NMR (400 MHz, DMSO-d₆) δ:8.20 (s, 2H), 3.90 (s, 6H), 3.81 (s, 3H). LC-MS: m/z 198.1 (M+H)⁺

Step D: 3,5-Dimethoxyisonicotinic acid

A solution of methyl 3,5-dimethoxyisonicotinate (5.50 g, 28.0 mmol, 1.0equiv) in THF (20 mL) and H₂O (10 mL) was added NaOH (2.24 g, 56.0 mmol,2.0 equiv). The mixture was stirred at 50° C. overnight. 10 mL HClsolution (5.6 mol/L in H₂O, 56.0 mmol, 2.0 equiv) was added and then themixture was concentrated under vacuum. The residue was used directly fornext step. LC-MS: m/z 184.1 (M+H)⁺

Step E: 3,5-Dimethoxypyridin-4-amine

To a solution of 3,5-dimethoxyisonicotinic acid (5.12 g, 28.0 mmol, 1equiv) in 50 mL THF was added Et₃N (12.7 g, 126 mmol, 17.4 mL, 4.5equiv) and DPPA (11.6 g, 42.0 mmol, 1.5 equiv) under N₂. The mixture wasstirred at 70° C. for 2 hours under N₂, and then H₂O (10 mL) was added.The reaction mixture was stirred overnight. The resulting mixture wasextracted with DCM (50 mL*3). The combined organic phase was washed withbrine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated.The residue was purified by flash chromatography on silica gel (elutedwith DCM/MeOH=20/1) to afford 3,5-dimethoxypyridin-4-amine as a whitesolid (2.46 g, 57% yield in two steps). ¹H NMR (400 MHz, DMSO-d₆) δ:7.76 (s, 2H), 5.13 (s, 2H), 3.82 (s, 6H). LC-MS: m/z 155.1 (M+H)⁺

Example 117:N-(5-Chloro-1-(3,5-dimethoxypyridin-4-yl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

The title compound was prepared according to Method K, step B, startingfrom N-(3,5-dibromo-6-chloropyrazin-2-yl)-6-ethoxypicolinamide by using3,5-dimethoxypyridin-4-amine. ¹H NMR (400 MHz, Chloroform-d) δ: 8.21 (s,2H), 8.10 (d, J=7.2 Hz, 1H), 7.72 (t, J=8.0 Hz, 1H), 7.52 (s, 1H), 6.75(d, J=8.4 Hz, 1H), 3.76 (s, 6H), 3.36 (q, J=7.2 Hz, 2H), 3.24 (s, 3H),1.10 (t, J=7.2 Hz, 3H). LC-MS: m/z 506.1 (M+H)⁺

Example 118:N-(5-Chloro-1-(3,5-dimethoxypyridin-4-yl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)cyclopropanesulfonamide

The title compound was prepared according to Method K, starting fromN-(3,5-dibromo-6-chloropyrazin-2-yl)-6-ethoxypicolinamide by using3,5-dimethoxypyridin-4-amine in step B and cyclopropanesulfonamide atstep D. ¹H NMR (400 MHz, Chloroform-d) δ: 8.20 (s, 2H), 8.11 (d, J=7.6Hz, 1H), 7.71 (t, J=7.6 Hz, 1H), 6.74 (d, J=8.3 Hz, 1H), 3.75 (s, 6H),3.36 (q, J=7.2 Hz, 2H), 2.69 (tt, J=8.4, 4.8 Hz, 1H), 1.21 (dd, J=4.8,2.4 Hz, 2H), 1.11 (t, J=7.2 Hz, 3H), 0.88 (h, J=5.6 Hz, 2H). LC-MS: m/z532.1 (M+H)⁺

Method L

Step A: 6-Ethoxypicolinic acid

To a solution of ethyl 6-ethoxypicolinate (2.60 g, 13.3 mmol, 1.0 equiv)in EtOH (30 mL) was added sodium hydroxide solution (1 mol/L, 40.0 mL,40.0 mmol, 3 equiv). The reaction mixture was stirred at roomtemperature for 3 hours. The reaction mixture was acidified to pH=2 with1 N HCl aqueous solution and extracted with ethyl acetate (50 mL*3). Theorganic layer was washed with brine, dried over anhydrous MgSO₄, andconcentrated in vacuo to afford the title compound 6-ethoxypicolinicacid as a white solid (2.20 g, 100% yield).

Step B: 6-Ethoxypicolinoyl chloride

To the solution of 6-ethoxypicolinic acid (20.0 g, 120 mmol, 1.0 equiv)and C₂O₂Cl₂ (23.3 g, 180 mmol, 1.5 equiv) in DCM (100 mL) was added 6drops of DMF dropwise at 0° C. under argon atmosphere. The resultingmixture was stirred at 0° C. for 2 hours. The mixture was concentratedto give the crude product, which was used for next step directly.

Step C: N-(4-Bromo-6-chloropyridazin-3-yl)-6-ethoxypicolinamide

To the solution of 4-bromo-6-chloropyridazin-3-amine (25.1 g, 120 mmol,1.0 equiv) in THF (200 mL) was added NaH (60% in mineral oil) (14.4 g,360 mmol, 3.0 equiv) at 0° C. The resulting mixture was stirred at roomtemperature for 1 hour. 6-Ethoxypicolinoyl chloride (22.2 g, 120 mmol,1.0 equiv) in DCM (30 mL) was added to the above mixture dropwise at 0°C. and then the mixture was stirred at room temperature overnight. Themixture was quenched with saturated NH₄Cl solution. The mixture wasextracted with DCM (100 mL*3). The combined organic layers were washedwith brine, dried and concentrated. The residue was purified by columnchromatography (eluted with PE/EtOAc=1/1) to affordN-(4-bromo-6-chloropyridazin-3-yl)-6-ethoxypicolinamide as a white solid(29.5 g, 69% yield). LC-MS: m/z 356.9, 358.9 (M+H)⁺

Step D:N-(6-Chloro-4-((2,6-dimethoxyphenyl)amino)pyridazin-3-yl)-6-ethoxypicolinamide

A suspension of N-(4-bromo-6-chloropyridazin-3-yl)-6-ethoxypicolinamide(1.07 g, 3.00 mmol, 1.0 equiv), 2,6-dimethoxyaniline (688 mg, 4.50 mmol,1.5 equiv), Pd₂(dba)₃ (275 mg, 0.300 mmol, 0.1 equiv), Xantphos (695 mg,1.20 mmol, 0.4 equiv) and K₂CO₃ (828 mg, 6.0 mmol, 2.0 equiv) in1,4-dioxane (15 mL) was stirred at 120° C. via microwave irradiationunder N₂ atmosphere for 3 hours. The mixture was filtered through celiteand the filtrate was concentrated in vacuo. The residue was purified byflash chromatography (eluted with PE/EtOAc=3/1) to affordN-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamideas a yellow solid (800 mg, 62% yield). LC-MS: m/z 430.1 (M+H)⁺

Step E:Chloro-7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazine

A solution ofN-(6-chloro-4-((2,6-dimethoxyphenyl)amino)pyridazin-3-yl)-6-ethoxypicolinamide(110 mg, 0.250 mmol) in AcOH (10 mL) was stirred at 120° C. viamicrowave irradiation for 2 hours. After the reaction mixture was cooledto room temperature, the light yellow precipitate was filtered off andrinsed with EtOAc/PE=1/2 (5 mL*2) to affordchloro-7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazineas light yellow solid (70.0 mg, 67% yield). ¹H NMR (400 MHz, DMSO-d₆) δ:8.05 (dd, J=7.6, 0.8 Hz, 1H), 7.93 (dd, J=8.4, 7.6 Hz, 1H), 7.67 (s,1H), 7.50 (t, J=8.4 Hz, 1H), 6.93 (dd, J=8.4, 0.8 Hz, 1H), 6.89 (d,J=8.4 Hz, 2H), 3.60 (s, 6H), 3.40 (q, J=7.2 Hz, 2H), 1.04 (t, J=7.2 Hz,3H). LC-MS: m/z 412.1 (M+H)⁺

Step F:N-(7-(2,6-Dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazinyl)methanesulfonamide(Example 21)

A suspension ofchloro-7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazine(48.0 mg, 0.120 mmol, 1.0 equiv), methanesulfonamide (22.0 mg, 0.230mmol, 2.0 equiv), CuI (44.0 mg, 0.230 mmol, 2.0 equiv), trans-N,N′-Dimethylcyclohexane-1, 2-diamine (33.0 mg, 0.230 mmol, 2.0 equiv) andK₂CO₃ (49.7 mg, 0.36 mmol, 3 equiv) in DMF (2 mL) was stirred at 130° C.via microwave irradiation for 1.5 hour under N₂ atmosphere. The reactionsolution was diluted with water (10 mL) and extracted with EtOAc (10mL*3). The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified byflash chromatography (eluted with DCM/MeOH=100/1) to affordN-(7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazinyl)methanesulfonamideas a yellow solid (30.0 mg, 55% yield). ¹H NMR (400 MHz, DMSO-d₆) δ:10.78 (s, 1H), 8.01 (dd, J=7.6, 0.8 Hz, 1H), 7.91 (t, J=8.0 Hz, 1H),7.50 (t, J=8.4 Hz, 1H), 6.85-6.97 (m, 4H), 3.61 (s, 6H), 3.39 (q, J=7.2Hz, 2H), 3.22 (s, 3H), 1.03 (t, J=7.2 Hz, 3H). LC-MS: m/z 471.1 (M+H)⁺

Example 119:N-(7-(2,6-Dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazinyl)cyclopropanesulfonamide

The title compound was prepared according to Method L, step F, startingfromchloro-7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazineby using cyclopropanesulfonamide. ¹H NMR (400 MHz, Chloroform-d) δ: 8.11(dd, J=7.2, 0.8 Hz, 1H), 7.71 (dd, J=8.4, 7.2 Hz, 1H), 7.38 (t, J=8.4Hz, 1H), 6.91 (s, 1H), 6.77 (dd, J=8.4, 0.8 Hz, 1H), 6.66 (d, J=8.4 Hz,2H), 3.64 (s, 6H), 3.39 (q, J=7.2 Hz, 2H), 2.55-2.59 (m, 1H), 1.19-1.21(m, 2H), 1.08 (t, J=7.2 Hz, 3H), 0.95-0.98 (m, 2H). LC-MS: m/z 497.1(M+H)⁺

Example 120:N-(7-(2,6-Dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazinyl)-5-fluoropyridine-2-sulfonamide

The title compound was prepared according to Method L, step F, startingfromchloro-7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazineby using 5-fluoropyridine-2-sulfonamide. ¹H NMR (400 MHz, Chloroform-d)δ: 8.13-8.83 (m, 2H), 8.11 (d, J=7.2 Hz, 1H), 7.73 (t, J=8.0 Hz, 1H),7.57 (t, J=7.6 Hz, 1H), 7.38 (t, J=8.4 Hz, 1H), 6.80-6.93 (m, 1H), 6.79(d, J=8.0 Hz, 1H), 6.65 (d, J=8.4 Hz, 2H), 3.63 (s, 6H), 3.38 (q, J=7.2Hz, 2H), 1.07 (t, J=7.2 Hz, 3H). LC-MS: m/z 552.1 (M+H)⁺

Example 121:N-(7-(2,6-Dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazinyl)morpholine-4-sulfonamide

The title compound was prepared according to Method L, step F, startingfromchloro-7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazineby using morpholine-4-sulfonamide. ¹H NMR (400 MHz, Chloroform-d) δ:11.89 (br. s, 1H), 8.09 (d, J=7.2 Hz, 1H), 7.71 (t, J=7.6 Hz, 1H), 7.39(t, J=8.4 Hz, 1H), 6.78 (d, J=8.0 Hz, 1H), 6.74 (s, 1H), 6.67 (d, J=8.4Hz, 2H), 3.73 (t, J=4.8 Hz, 4H), 3.65 (s, 6H), 3.38 (q, J=7.2 Hz, 2H),3.20 (t, J=4.8 Hz, 4H), 1.08 (t, J=7.2 Hz, 3H). LC-MS: m/z 542.2 (M+H)⁺

Example 122:N-(7-(2,6-Dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazinyl)-1-(4-fluorophenyl)methanesulfonamide

The title compound was prepared according to Method L, step F, startingfromchloro-7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazineby using (4-fluorophenyl)methanesulfonamide. ¹H NMR (400 MHz, DMSO-d₆)δ: 7.99 (d, J=7.2 Hz, 1H), 7.91 (t, J=8.0 Hz, 1H), 7.50 (t, J=8.4 Hz,1H), 7.37-7.27 (m, 2H), 7.05 (br. s, 2H), 6.95-6.86 (m, 3H), 6.77 (br.s, 1H), 4.59 (br. s, 2H), 3.60 (s, 6H), 3.38 (q, J=7.2 Hz, 2H), 1.03 (t,J=7.2 Hz, 3H). LC-MS: m/z 565.1 (M+H)⁺

(5-Chloropyridin-2-yl)methanesulfonamide

5-Chloropyridin-2-yl)methanesulfonamide was prepared according to thepreparation of (3-fluoropyridin-2-yl)methanesulfonamide by using(5-chloropyridin-2-yl)methanol at step A. ¹H NMR (400 MHz, DMSO-d₆) δ:8.61 (d, J=2.4 Hz, 1H), 7.98 (dd, J=8.0 Hz, 2.8 Hz, 1H), 7.52 (d, J=8.0Hz, 1H), 6.95 (s, 2H), 4.45 (s, 2H). LC-MS: m/z 207.0 (M+H)⁺

Example 123:1-(5-Chloropyridin-2-yl)-N-(7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazinyl)methanesulfonamide

The title compound was prepared according to Method L, step F, startingfromchloro-7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazineby using (5-chloropyridin-2-yl)methanesulfonamide. ¹H NMR (400 MHz,Chloroform-d) δ: 8.43 (s, 1H), 8.08 (d, J=7.2 Hz, 1H), 7.71 (t, J=8.0Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.39 (t, J=8.4Hz, 1H), 6.78 (d, J=8.0 Hz, 2H), 6.66 (d, J=8.4 Hz, 2H), 4.56 (s, 2H),3.65 (s, 6H), 3.40 (q, J=7.2 Hz, 2H), 1.08 (t, J=7.2 Hz, 3H). LC-MS: m/z582.2 (M+H)⁺

Example 124:N-(7-(2,6-Dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazinyl)-1-(S-methylpyridin-2-y)methanesulfonamide

The title compound was prepared according to Method L, step F, startingfromchloro-7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazineby using (5-methylpyridin-2-yl)methanesulfonamide. ¹H NMR (400 MHz,DMSO-d₆) δ: 12.46 (br. s, 1H), 8.24 (s, 1H), 7.99 (d, J=7.2 Hz, 1H),7.91 (t, J=8.0 Hz, 1H), 7.43-7.56 (m, 2H), 7.33 (d, J=8.0 Hz, 1H), 6.92(d, J=7.6 Hz, 1H), 6.91 (d, J=8.4 Hz, 2H), 6.89 (s, 1H), 4.68 (s, 2H),3.61 (s, 6H), 3.38 (q, J=7.2 Hz, 2H), 2.22 (s, 3H), 1.03 (t, J=7.2 Hz,3H). LC-MS: m/z 562.2 (M+H)⁺

Example 125:N-(7-(2,6-Dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazinyl)-1-(5-fluoropyridin-2-y)methanesulfonamide

The title compound was prepared according to Method L, step F, startingfromchloro-7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazineby using (5-fluoropyridin-2-yl)methanesulfonamide. ¹H NMR (400 MHz,Chloroform-d) δ: 8.31 (br. s, 1H), 8.08 (d, J=7.6 Hz, 1H), 7.71 (t,J=8.0 Hz, 1H), 7.52-7.67 (m, 1H), 7.39 (t, J=8.4 Hz, 1H), 7.30-7.36 (m,1H), 6.78 (d, J=8.0 Hz, 1H), 6.79 (s, 1H), 6.66 (d, J=8.4 Hz, 2H), 4.60(s, 2H), 3.65 (s, 6H), 3.38 (q, J=8.0 Hz, 2H), 1.08 (t, J=8.0 Hz, 3H).LC-MS: m/z 566.2 (M+H)⁺

Example 126:N-(7-(2,6-Dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazinyl)-1-(S-methylpyrimidin-2-yl)methanesulfonamide

The title compound was prepared according to Method L, step F, startingfromchloro-7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazineby using (5-methylpyrimidin-2-yl)methanesulfonamide. ¹H NMR (400 MHz,DMSO-d₆) δ: 8.52 (s, 2H), 7.99 (d, J=7.2 Hz, 1H), 7.91 (t, J=8.0 Hz,1H), 7.51 (t, J=8.4 Hz, 1H), 6.90-6.93 (m, 4H), 4.80 (br. s, 2H), 3.61(s, 6H), 3.39 (q, J=7.2 Hz, 2H), 2.20 (s, 3H), 1.03 (t, J=7.2 Hz, 3H).LC-MS: m/z 563.2 (M+H)⁺

Example 127:N-(5-(2,6-Dimethoxyphenyl)-6-(6-ethoxypyridin-2-yl)-5H-imidazo[4,5-c]pyridazin-3-yl)-1-(pyrimidin-2-yl)methanesulfonamide

The title compound was prepared according to Method L, step F, startingfromchloro-7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazineby using pyrimidin-2-ylmethanesulfonamide. ¹H NMR (400 MHz,Chloroform-d) δ: 8.72 (d, J=4.4 Hz, 2H), 8.08 (d, J=7.2 Hz, 1H), 7.71(t, J=8.0 Hz, 1H), 7.39 (t, J=8.4 Hz, 1H), 7.20 (t, J=4.4 Hz, 1H), 6.92(s, 1H), 6.77 (d, J=8.0 Hz, 1H), 6.67 (d, J=8.4 Hz, 2H), 4.80 (s, 2H),3.65 (s, 6H), 3.39 (q, J=7.2 Hz, 2H), 1.08 (t, J=7.2 Hz, 3H). LC-MS: m/z549.2 (M+H)⁺

Example 128:N-(5-(2,6-Dimethoxyphenyl)-6-(6-ethoxypyridin-2-yl)-5H-imidazo[4,5-c]pyridazin-3-yl)-1-(3-hydroxy-3-methylcyclobutyl)methanesulfonamide

The title compound was prepared according to Example 81 usingchloro-7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazinein step H. ¹H NMR (400 MHz, Chloroform-d) δ: 8.03 (d, J=7.2 Hz, 1H),7.65 (t, J=7.2 Hz, 1H), 7.32 (t, J=8.4 Hz, 1H), 6.77 (s, 1H), 6.72 (d,J=8.0 Hz, 1H), 6.60 (d, J=8.8 Hz, 2H), 3.58 (s, 6H), 3.31 (q, J=7.2 Hz,2H), 3.20 (d, J=7.2 Hz, 2H), 2.24-2.28 (m, 3H), 1.82-1.87 (m, 2H), 1.30(s, 3H), 1.08 (t, J=7.2 Hz, 3H). LC-MS: m/z 555.1 (M+H)⁺

Example 129:N-(7-(2,6-Dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazinyl)-1-(5-hydroxypyrimidin-2-yl)methanesulfonamide

The title compound was a byproduct prepared according to Method L, stepF, starting fromchloro-7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazineby using (5-fluoropyrimidin-2-yl)methanesulfonamide. ¹H NMR (400 MHz,Chloroform-d) δ: 8.26 (s, 2H), 8.00 (s, 2H), 7.66-7.70 (m, 1H), 7.14 (t,J=8.4 Hz, 1H), 6.69-6.77 (m, 2H), 5.98 (d, J=8.0 Hz, 1H), 5.27 (br. s,1H), 3.91 (s, 3H), 3.73 (q, J=6.8 Hz, 2H), 3.38-3.42 (m, 1H), 3.18 (s,3H), 3.06-3.10 (m, 1H), 1.03 (t, J=6.8 Hz, 3H). LC-MS: m/z 565.1 (M+H)⁺

Step A: 5-Methylfuran-2-carbonyl chloride

To a solution of 5-methylfuran-2-carboxylic acid (1.50 g, 11.9 mmol, 1.0equiv) and oxalyl chloride (3.00 g, 23.8 mmol, 2.0 equiv) in DCM (20 mL)was added DMF (0.1 mL) at 0° C. The resulting mixture was stirred at 0°C. for 1 hour. The reaction mixture was concentrated in vacuo to afford5-methylfuran-2-carbonyl chloride which was used for next step directly.

Step B: N-(4-Bromo-6-chloropyridazin-3-yl)-5-methylfuran-2-carboxamide

To a solution of 4-bromo-6-chloropyridazin-3-amine (2.40 g, 11.9 mmol,1.0 equiv) in THF (20 mL) was added NaH (60% in mineral oil) (857 mg,34.8 mmol, 3 equiv) at 0° C. The mixture was stirred at room temperaturefor 1 hour, and then a solution of 5-methylfuran-2-carbonyl chloride inDCM (10 mL) was added dropwise. The mixture was stirred at roomtemperature for 2 hours. The reaction mixture was quenched withsaturated ammonium chloride solution (10 mL) and extracted with DCM (50mL*3). The combined organic layers were washed with brine (20 mL), driedover anhydrous Na₂SO₄, and concentrated in vacuo. The residue waspurified by flash chromatography on silica gel (eluted withEtOAc/PE=2/3) to affordN-(4-bromo-6-chloropyridazin-3-yl)-5-methylfuran-2-carboxamide as alight yellow solid (2.20 g, 58% yield). LC-MS: m/z 315.9, 317.9 (M+H)⁺

Step C:N-(6-Chloro-4-((2,6-dimethoxyphenyl)amino)pyridazin-3-yl)-5-methylfuran-2-carboxamide

A suspension ofN-(4-bromo-6-chloropyridazin-3-yl)-5-methylfuran-2-carboxamide (1.20 g,3.80 mmol, 1.0 equiv), 2,6-dimethoxyaniline (583 mg, 3.80 mmol, 1.0equiv), Pd(OAc)₂ (170 mg, 0.760 mmol, 0.2 equiv), Xantphos (880 mg, 1.50mmol, 0.4 equiv) and K₂CO₃ (1.05 g, 7.60 mmol, 2.0 equiv) in 1,4-dioxane(10 mL) was stirred at 100° C. via microwave irradiation for 3 hoursunder N₂ atmosphere. The mixture was filtered through celite and thefiltrate was concentrated in vacuo. The residue was purified by flashchromatography (EtOAc/PE=1/2) to affordN-(6-chloro-4-((2,6-dimethoxyphenyl)amino)pyridazin-3-yl)-5-methylfuran-2-carboxamideas a yellow solid (330 mg, 22% yield). LC-MS: m/z 389.1, 391.1 (M+H)⁺

Step D:Chloro-7-(2,6-dimethoxyphenyl)-8-(5-methylfuran-2-yl)-7H-imidazo[4,5-c]pyridazine

A solution ofN-(6-chloro-4-((2,6-dimethoxyphenyl)amino)pyridazin-3-yl)-5-methylfuran-2-carboxamide(300 mg, 0.770 mmol) in AcOH (10 mL) was stirred at 120° C. viamicrowave irradiation for 2 hours. After the reaction solution wascooled to room temperature, the light yellow precipitate was filteredoff and rinsed with (eluted with DCM/MeOH=100/1) to affordchloro-7-(2,6-dimethoxyphenyl)-8-(5-methylfuran-2-yl)-7H-imidazo[4,5-c]pyridazineas a light yellow solid (200 mg, 70% yield). LC-MS: m/z 371.1 (M+H)⁺

Step E:N-(7-(2,6-Dimethoxyphenyl)-8-(5-methylfuran-2-yl)-7H-imidazo[4,5-c]pyridazinyl)methanesulfonamide(Example 130)

A suspension ofchloro-7-(2,6-dimethoxyphenyl)-8-(5-methylfuran-2-yl)-7H-imidazo[4,5-c]pyridazine(200 mg, 0.540 mmol, 1.0 equiv), methanesulfonamide (102 mg, 1.08 mmol,2.0 equiv), CuI (103 mg, 0.540 mmol, 1.0 equiv), trans-N,N′-Dimethylcyclohexane-1, 2-diamine (77.0 mg, 0.540 mmol, 1.0 equiv) andK₂CO₃ (224 mg, 1.62 mmol, 3.0 equiv) in DMF (10 mL) was stirred at 140°C. via microwave irradiation for 4 hour under N₂ atmosphere. Thereaction solution was diluted with water (50 mL) and extracted withEtOAc (50 mL*3). The combined organic layers were washed with brine,dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by pre-HPLC to affordN-(7-(2,6-dimethoxyphenyl)-8-(5-methylfuran-2-yl)-7H-imidazo[4,5-c]pyridazinyl)methanesulfonamideas a yellow solid (70.0 mg, 30% yield). ¹HNMR (400 MHz, DMSO-d₆) δ: 7.66(t, J=8.4 Hz, 1H), 6.99 (d, J=8.4 Hz, 2H), 6.91 (s, 1H), 6.39 (d, J=3.6Hz, 1H), 6.28-6.33 (m, 1H), 3.69 (s, 6H), 3.13 (s, 3H), 2.30 (s, 3H).LC-MS: m/z 430.0 (M+H)⁺

Method M

Step A: N-(3-Bromo-5-chloropyrazin-2-yl)acetamide

To a solution of compound 3-bromo-5-chloropyrazin-2-amine (12.4 g, 60mmol, 1.0 equiv) in anhydrous THF (100 mL) was added NaH (60% in mineraloil, 7.20 g, 180 mmol, 3.0 equiv). The resulting mixture was stirred at0° C. for 1 hour. Then acetic anhydride (6.80 mL, 72.0 mmol, 1.2 equiv)was added dropwise to the mixture and the mixture was stirred at roomtemperature for 12 hours. The mixture was quenched with 1N HCl (200 mL)and extracted with EtOAc (300 mL*3). The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by flash chromatography on silica gel(eluted with PE/EtOAc=3/1) to giveN-(3-bromo-5-chloropyrazin-2-yl)acetamide as a white solid (10.0 g, 67%yield). LC-MS: m/z 249.9, 251.9 (M+H)⁺

Step B: N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)acetamide

A suspension of N-(3-bromo-5-chloropyrazin-2-yl)acetamide (11.5 g, 46.4mmol, 1.0 equiv), 2,6-dimethoxyaniline (7.10 g, 46.4 mmol, 1.0 equiv),Pd(OAc)₂ (2.10 g, 9.28 mmol, 0.2 equiv), Xantphos (8.06 g, 13.9 mmol,0.3 equiv) and K₂CO₃ (12.8 g, 92.8 mmol, 2.0 equiv) in 1,4-dioxane (80mL) was stirred at 110° C. for 3 hours under N₂ atmosphere. The mixturewas filtered through celite and the filtrate was concentrated in vacuo.The residue was purified by flash chromatography on silica gel (elutedwith PE/EtOAc=2/1) to giveN-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)acetamide as ayellow solid (4.48 g, 30% yield). LC-MS: m/z 323.1 (M+H)⁺

Step C: 6-chloro-N₂-(2,6-dimethoxyphenyl)pyrazine-2, 3-diamine

A mixture of N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)acetamide (1.70 g, 5.30 mmol, 1.0 equiv) and con. HCl (20 mL) in EtOH(30 mL) was refluxed at 100° C. for 4 hours. The reaction mixture wascooled to room temperature and then basified with 2N NaOH aqueoussolution to pH=8˜9. The mixture was extracted with EtOAc (80 mL*3). Thecombined organic phase was washed with brine (30 mL), dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified byflash chromatography on silica gel (eluted with PE/EtOAc=3/1) to give6-chloro-N2-(2,6-dimethoxyphenyl)pyrazine-2, 3-diamine as a yellow solid(1.10 g, 74% yield). LC-MS: m/z 281.0 (M+H)⁺

Step D:6-chloro-1-(2,6-dimethoxyphenyl)-2-(5-methylfuran-2-yl)-1H-imidazo[4,5-b]pyrazine

A mixture of 6-chloro-N²-(2,6-dimethoxyphenyl)pyrazine-2, 3-diamine (500mg, 1.78 mmol, 1.0 equiv) and 5-methylfuran-2-carboxylic acid (1.12 g,8.90 mmol, 5.0 equiv) in POCl₃ (10 mL) was stirred at 100° C. overnightunder nitrogen atmosphere. The reaction mixture was concentrated invacuo. The residue was redissolved in DCM, basified with 1 mol/L NaOHaqueous solution to pH=6. The organic phase was separated, dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified byflash chromatography on silica gel (eluted with PE/EtOAc=1/1) to afford6-chloro-1-(2,6-dimethoxyphenyl)-2-(5-methylfuran-2-yl)-1H-imidazo[4,5-b]pyrazineas a pale white solid (100 mg, 15% yield). LC-MS: m/z 371.1 (M+H)⁺

Step E:N-(1-(2,6-dimethoxyphenyl)-2-(5-methylfuran-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide(Example 131)

A suspension of6-chloro-1-(2,6-dimethoxyphenyl)-2-(5-methylfuran-2-yl)-1H-imidazo[4,5-b]pyrazine(100 mg, 0.270 mmol, 1.0 equiv), methanesulfonamide (128 mg, 1.35 mmol,5.0 equiv), CuI (102 mg, 0.540 mmol, 2.0 equiv), trans-N,N′-Dimethylcyclohexane-1, 2-diamine (76.0 mg, 0.540 mmol, 2.0 equiv) andK₂CO₃ (111 mg, 0.810 mmol, 3 equiv) in DMF (5 mL) was stirred at 120° C.via microwave irradiation for 2 hours under N₂ atmosphere. The mixturewas diluted with H₂O (20 mL), adjusted with HCOOH to pH=5, followed byextraction with DCM (20 mL*3). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by pre-HPLC (eluted with CH₃CN/H₂O=5/95˜90/10including 0.1% HCOOH) to affordN-(1-(2,6-dimethoxyphenyl)-2-(5-methylfuran-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamideas a white solid (45.0 mg, 39% yield). ¹HNMR (400 MHz, DMSO-do) S: 10.68(br. s, 1H), 8.23 (s, 1H), 7.60 (t, J=8.4 Hz, 1H), 6.94 (d, J=8.4 Hz,2H), 6.19-6.26 (m, 2H), 3.65 (s, 6H), 3.15 (s, 3H), 2.29 (s, 3H). LC-MS:m/z 430.0 (M+H)⁺

Example 132:N-(1-(2,6-dimethoxyphenyl)-2-(5-methylpyridin-3-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

The title compound was prepared according to Method M, step D, startingfrom 6-chloro-N₂-(2,6-dimethoxyphenyl)pyrazine-2, 3-diamine by using5-methylnicotinic acid. ¹HNMR (400 MHz, DMSO-d₆) δ: 11.06 (s, 1H), 8.49(d, J=1.6 Hz, 1H), 8.39 (d, J=1.6 Hz, 1H), 8.30 (s, 1H), 7.87-7.83 (m,1H), 7.55 (t, J=8.4 Hz, 1H), 6.89 (d, J=8.4 Hz, 2H), 3.61 (s, 6H), 3.21(s, 3H), 2.29 (s, 3H). LC-MS: m/z 441.0 (M+H)⁺

Example 133:N-(1-(2,6-dimethoxyphenyl)-2-(5-methylpyridin-3-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)cyclopropanesulfonamide

The title compound was prepared according to Method M, by using5-methylnicotinic acid at step D and cyclopropanesulfonamide at step E.¹H NMR (400 MHz, DMSO-d₆) δ: 11.05 (s, 1H), 8.48 (d, J=1.6 Hz, 1H), 8.41(d, J=1.6 Hz, 1H), 8.31 (s, 1H), 7.86 (s, 1H), 7.56 (t, J=8.4 Hz, 1H),6.90 (d, J=8.4 Hz, 2H), 3.62 (s, 6H), 2.76-2.82 (m, 1H), 2.29 (s, 3H),0.99-0.83 (m, 4H). LC-MS: m/z 467.0 (M+H)⁺

Step A:6-chloro-1-(2,6-dimethoxyphenyl)-1H-imidazo[4,5-b]pyrazine-2-thiol

To a solution of 6-chloro-N₂-(2,6-dimethoxyphenyl)pyrazine-2, 3-diamine(1.12 g, 4 mmol, 1.0 equiv) in anhydrous THF (50 mL) was added NaH (60%in mineral oil, 1.60 g, 40.0 mmol, 10.0 equiv). The resulting mixturewas stirred at 0° C. for 0.5 hour under N₂ atmosphere. Thendi(1H-imidazol-1-yl)methanethione (1.42 g, 8.00 mmol, 2.0 equiv) wasadded at 0° C. The resulting mixture was then refluxed at 65° C. for 3hours. The reaction mixture was cooled to room temperature and thenadjusted with 2 N HCl aqueous solution to pH=5˜6. The mixture wasextracted with EtOAc (50 mL*3). The combined organic phase was washedwith brine (30 mL), dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by flash chromatography on silica gel(eluted with PE/EtOAc=3/1) to give6-chloro-1-(2,6-dimethoxyphenyl)-1H-imidazo[4,5-b]pyrazine-2-thiol (1.0g, 77% yield) as a yellow solid. LC-MS: m/z 323.1 (M+H)⁺

Step B:6-Chloro-1-(2,6-dimethoxyphenyl)-2-(methylthio)-1H-imidazo[4,5-b]pyrazine

To a mixture of 6-chloro-1-(2,6-dimethoxyphenyl)-1H-imidazo[4,5-b]pyrazine-2-thiol (1.40 g, 4.30 mmol, 1.0 equiv) and K₂CO₃ (1.80 g, 12.9mmol, 3.0 equiv) in anhydrous THF (20 mL) was added CH₃₁ (3.10 g, 21.5mmol, 5.0 equiv) at 0° C. under N₂ atmosphere. The reaction mixture wasstirred at room temperature for 2 h. The mixture was concentrated andresidue was purified by flash chromatography on silica gel (eluted withPE/EtOAc=1/2) to give6-chloro-1-(2,6-dimethoxyphenyl)-2-(methylthio)-1H-imidazo[4,5-b]pyrazineas a yellow solid (1.10 g, 75% yield). LC-MS: m/z 337.0, 339.0 (M+H)⁺

Step C:6-Chloro-1-(2,6-dimethoxyphenyl-2-(methylsulfonyl)-1H-imidazo[4,5-b]pyrazine

A solution of compound6-chloro-1-(2,6-dimethoxyphenyl)-2-(methylthio)-1H-imidazo[4,5-b]pyrazine(1.18 g, 3.50 mmol, 1.0 equiv) and m-CPBA (85% purity) (1.56 g, 7.70mmol, 2.2 equiv) in DCM (20 mL) was stirred at 0° C. for 5 h. Thereaction was diluted with DCM (20 mL), washed with saturated Na₂S₂O₃aqueous solution, Na₂CO₃ aqueous solution, brine, dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by flashchromatography on silica gel (eluted with PE/EtOAc=1/3) to give6-chloro-1-(2,6-dimethoxyphenyl)-2-(methylsulfonyl)-1H-imidazo[4,5-b]pyrazine as a yellow solid (400 mg, 31% yield). LC-MS: m/z 369.1, 371.1(M+H)⁺

Step D:6-Chloro-1-(2,6-dimethoxyphenyl)-2-propoxy-1H-imidazo[4,5-b]pyrazine

A mixture of K₂CO₃ (225 mg, 1.63 mmol, 1.5 equiv) in 1-propanol (10 mL)was stirred at room temperature for 0.5 h. Then6-chloro-1-(2,6-dimethoxyphenyl)-2-(methylsulfonyl)-1H-imidazo[4,5-b]pyrazine (400 mg 1.09 mmol, 1.0 equiv) in 1-propanol(10 mL) was added to the mixture. The resulting mixture was stirred atroom temperature for 1 h. The reaction mixture was concentrated and theresidue was purified by flash chromatography on silica gel (eluted withPE/EtOAc=100/1) to give6-chloro-1-(2,6-dimethoxyphenyl)-2-propoxy-1H-imidazo[4,5-b]pyrazine asa white solid (200 mg, 53% yield). LC-MS: m/z 349.0, 351.0 (M+H)⁺

Step E:N-(1-(2,6-Dimethoxyphenyl)-2-propoxy-1H-imidazo[4,5-b]pyrazin-6-yl)benzenesulfonamide(Example 134)

A mixture of6-chloro-1-(2,6-dimethoxyphenyl)-2-propoxy-1H-imidazo[4,5-b]pyrazine(100 mg, 0.287 mmol, 1.0 equiv), benzenesulfonamide (90 mg, 0.574 mmol,2.0 equiv), CuI (109 mg, 0.574 mmol, 2.0 equiv), trans-N,N′-Dimethylcyclohexane-1, 2-diamine (82 mg, 0.574 mmol, 2.0 equiv) andK₂CO₃ (119 mg, 0.861 mmol, 3.0 equiv) in DMF (1.5 mL) was stirred at115° C. via microwave irradiation for 8 h under N₂ atmosphere. Thereaction mixture was acidified to pH=4˜6 with 2 N HCl aqueous solutionand concentrated. The residue was purified by flash chromatography onsilica gel (eluted with PE/EtOAc=1/1) to giveN-(1-(2,6-dimethoxyphenyl)-2-propoxy-1H-imidazo[4,5-b]pyrazin-6-yl)benzenesulfonamideas white solid (9.00 mg, 7% yield).

¹H NMR (400 MHz, Chloroform-d) δ: 9.35 (br. s, 1H), 8.38 (s, 1H), 7.66(d, J=4.0 Hz, 2H), 7.40-7.44 (m, 2H), 7.26-7.31 (m, 1H), 6.66 (d, J=8.0Hz, 2H), 3.73 (s, 6H), 3.45 (t, J=4.0 Hz, 2H), 1.37-1.47 (m, 2H), 0.84(t, J=4.0 Hz, 3H). LC-MS: m/z 470.0 (M+H)⁺

Example 135:N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-5-hydroxy-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

A suspension ofN-(5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide(200 mg, 0.400 mmol, 1.0 equiv), water (36.0 mg, 2.00 mmol, 5 equiv),CuI (152 mg, 0.800 mmol, 2.0 equiv), trans-N, N′-Dimethylcyclohexane-1,2-diamine (114 mg, 0.800 mmol, 2.0 equiv) and K₂CO₃ (276 mg, 2.00 mmol,5 equiv) in DMF (3 mL) was stirred at 100° C. via microwave irradiationfor 2 hours under N₂ atmosphere. The reaction was diluted with water (60mL), followed by extraction with EtOAc (60 mL*3). The combined organiclayer was dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by flash chromatography (eluted withDCM/MeOH=80/1˜20/1) to giveN-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-5-hydroxy-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamideas a yellow solid (21.0 mg, 11% yield). ¹H NMR (400 MHz, DMSO-d₆)δ:10.15 (s, 1H), 7.69-7.77 (m, 2H), 7.42 (t, J=8.4 Hz, 1H), 6.83 (d,J=8.4 Hz, 2H), 6.68 (d, J=8.0 Hz, 1H), 3.58 (s, 6H), 3.37 (q, J=7.2 Hz,2H), 3.15 (s, 3H), 0.99 (t, J=7.2 Hz, 3H). LC-MS: m/z 487.1 (M+H)⁺

Example 136:N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-5-(3-hydroxyazetidin-1-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

A suspension ofN-(5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide(270 mg, 0.534 mmol, 1.0 equiv), azetidin-3-ol hydrochloride (176 mg,1.60 mmol, 3.0 equiv), CuI (203 mg, 1.07 mmol, 2.0 equiv), trans-N,N′-Dimethylcyclohexane-1, 2-diamine (152 mg, 1.07 mmol, 2.0 equiv) andK₂CO₃ (369 mg, 2.67 mmol, 5 equiv) in DMF (6 mL) was stirred at 115° C.via microwave irradiation for 3.5 hours under N₂ atmosphere. Thereaction mixture was diluted with water (60 mL), followed by extractionwith EtOAc (60 mL*3). The combined organic layers were dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified byflash chromatography (eluted with DCM/MeOH=80/1˜20/1) and prep-HPLC togiveN-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-5-(3-hydroxyazetidin-1-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamideas yellow solid (1.2 mg, 0.4% yield). ¹H NMR (400 MHz, CD₃OD) δ:7.63-7.71 (m, 2H), 7.41 (t, J=8.4 Hz, 1H), 6.78 (d, J=8.4 Hz, 2H), 6.59(d, J=7.6 Hz, 1H), 4.77-4.82 (m, 1H), 4.58-4.62 (m, 2H), 4.39 (d, J=14.4Hz, 1H), 3.66-3.72 (m, 2H), 3.63 (s, 3H), 3.62 (s, 3H), 3.43 (q, J=7.2Hz, 2H), 2.98 (s, 3H), 1.04 (t, J=7.2 Hz, 3H). LC-MS: m/z 542.2 (M+H)⁺

Example 137:N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-5-vinyl-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

To a suspension ofN-(5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide(50.5 mg, 0.100 mmol, 1.0 equiv), 4, 4,5, 5-tetramethyl-2-vinyl-1, 3,2-dioxaborolane (20.0 μL, 0.120 mmol, 1.2 equiv), and K₃PO₄ (42.5 mg,0.200 mmol, 2.0 equiv) in THF/water (2.5 mL/0.6 mL) was addedPd(dppf)Cl₂ (7.30 mg, 0.0100 mmol, 0.1 equiv) at room temperature. Theresulting mixture was degassed and re-charged with N₂ for three timesand then stirred at 100° C. for 16 hours under N₂ atmosphere. Thereaction mixture was diluted with water (50 mL), followed by extractionwith EtOAc (50 mL*2). The combined organic layers were dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified byflash chromatography (eluted with DCM/MeOH=80/1˜25/1) to giveN-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-5-vinyl-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamideas yellow solid (20.0 mg, 40% yield). ¹H NMR (400 MHz, DMSO-d₆) δ: 10.44(s, 1H), 7.98 (d, J=6.4 Hz, 1H), 7.88 (t, J=8.0 Hz, 1H), 7.46 (t, J=8.0Hz, 1H), 7.24 (dd, J=10.8, 16.8 Hz, 1H), 6.84-6.87 (m, 3H), 6.42 (dd,J=2.4, 16.8 Hz, 1H), 5.57 (dd, J=2.0, 10.8 Hz, 1H), 3.57 (s, 6H), 3.39(q, J=6.8 Hz, 2H), 3.12 (s, 3H), 1.02 (t, J=6.8 Hz, 3H). LC-MS: m/z497.1 (M+H)⁺

Step A:5-Cloro-1-(2,6-dimethoxyphenyl-2-(6-ethoxypyridin-2-yl)-N-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyrazin-6-amine

A solution of6-bromo-5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine(1.00 g, 2.04 mmol, 1.0 equiv) in PMBNH₂ (10 mL) was stirred at 105° C.via microwave irradiation for 1 hour. The reaction mixture was dilutedwith H₂O (10 mL), adjusted with HCl (aq.) to pH=4˜6 and extracted withDCM (50 mL*3). The combined organic phase was washed with brine (30 mL),dried over anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by flash chromatography on silica gel (eluted withPFIEtOAc=1/1) to give5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-N-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyrazin-6-amineas a yellow solid (790 mg, 71% yield). LC-MS: m/z 547.1 (M+H)⁺

Step B:N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-6-((4-methoxybenzyl)amino)-1H-imidazo[4,5-b]pyrazin-5-yl)methanesulfonamide

A mixture of 5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-N-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyrazin-6-amine (790 mg,1.45 mmol, 1.0 equiv), methanesulfonamide (276 mg, 2.90 mmol, 2.0equiv), CuI (551 mg, 2.90 mmol, 2.0 equiv), trans-N,N′-Dimethylcyclohexane-1, 2-diamine (412 mg, 2.90 mmol, 2.0 equiv) andK₂CO₃ (600 mg, 4.35 mmol, 3.0 equiv) in DMF (1.5 mL) was stirred at 120°C. via microwave irradiation for 3 hours under N₂ atmosphere. Thereaction mixture was acidified to pH=4˜6 with HCOOH and concentrated.The residue was purified by flash chromatography on silica gel (elutedwith DCM/MeOH=10/1) to giveN-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-6-((4-methoxybenzyl)amino)-1H-imidazo[4,5-b]pyrazin-5-yl)methanesulfonamideas a yellow solid (350 mg, 39% yield). LC-MS: m/z 606.1 (M+H)⁺

Step C:N-(6-Amino-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)methanesulfonamide

A solution ofN-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-6-((4-methoxybenzyl)amino)-1H-imidazo[4,5-b]pyrazin-5-yl)methanesulfonamide(359 mg, 0.57 mmol) in TFA/DCM (5 mL/5 mL) was stirred at 50° C. for 1h. The reaction mixture was concentrated and residue was purified byflash chromatography on silica gel (eluted with DCM/MeOH=10/1) to giveN-(6-amino-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)methanesulfonamideas a yellow solid (160 mg, 58% yield). LC-MS: m/z 486.1 (M+H)⁺

Step D:N-(6-Chloro-1-(2,6-dimethoxyphenyl-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)methanesulfonamide(Example 138)

A mixture ofN-(6-amino-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)methanesulfonamide(160 mg, 0.33 mmol, 1.0 equiv), CuCl (130 mg, 1.32 mmol, 4.0 equiv), andCuCl₂ (265 mg, 1.98 mmol, 6.0 equiv) in CH₃CN (1.5 mL) was stirred atroom temperature for 0.5 h under N₂ atmosphere. Then isopentyl nitrite(231 mg, 1.98 mmol, 6.0 equiv) was added to the mixture and the reactionmixture was stirred at room temperature for 24 h. The reaction mixturewas concentrated and residue was purified by flash chromatography onsilica gel (eluted with DCM/MeOH=10/1) and prep-HPLC to giveN-(6-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)methanesulfonamideas white solid (3.00 mg, 1.8% yield). ¹H NMR (400 MHz, Chloroform-d) δ:8.10 (d, J=7.2 Hz, 1H), 7.68 (t, J=7.6 Hz, 1H), 7.42 (s, 1H), 7.38 (t,J=8.4 Hz, 1H), 6.72 (d, J=8.0 Hz, 1H), 6.68 (d, J=8.4 Hz, 1H), 3.66 (s,3H), 3.63 (s, 6H), 3.42 (q, J=8.0 Hz, 2H), 1.09 (t, J=8.0 Hz, 3H).LC-MS: m/z 505.1 (M+H)⁺

Step A: 6-Chloro-N-(3,5-dimethoxybenzyl)-5-methylpyridazin-3-amine

A mixture of 3, 6-dichloro-4-methylpyridazine (4.00 g, 24.7 mmol, 1.0equiv) and 2,4-dimethoxybenzylamine (32.8 g, 196 mmol, 8 equiv) inn-BuOH (40 mL) was stirred at 120° C. via microwave irradiation for 2hours. The mixture was concentrated and the residue was purified byflash chromatography (eluted with EtOAc/PE=2/3) to afford6-chloro-N-(3,5-dimethoxybenzyl)-5-methylpyridazin-3-amine as a lightyellow solid (6.20 g, 85.7% yield). LC-MS: m/z 294.0, 296.0 (M+H)⁺

Step B: 6-Chloro-5-methylpyridazin-3-amine

A solution of 6-chloro-N-(3,5-dimethoxybenzyl)-5-methylpyridazin-3-amine(6.20 g, 0.77 mmol, 1.0 equiv) in TFA (60 mL) was stirred at roomtemperature overnight. The mixture was concentrated and dissolved inDCM. The solution was basified to pH=6 with 1 mol/L NaOH aqueoussolution. The organic layer was separated, washed with brine, dried overanhydrous Na₂SO₄ and concentrated in vacuo and the residue wasreslurried in EtOAc to afford 6-chloro-5-methylpyridazin-3-amine aslight yellow solid (2.30 g, 79% yield). LC-MS: m/z 144.0, 146.0 (M+H)⁺

Step C: 4-Bromo-6-chloro-5-methylpyridazin-3-amine

The mixture of 6-chloro-5-methylpyridazin-3-amine and3-chloro-5-methylpyridazin-6-amine (2.30 g, 16.0 mmol, 1.0 equiv) andNaHCO₃ (8.40 g, 40.0 mmol, 2.5 equiv) in MeOH (100 mL) was treated withBr₂ (2.80 g, 17.6 mmol, 1.1 equiv) at 0° C. The mixture was stirred at0° C. for 4 h and then filtered. The filtrate was concentrated in vacuo.The residue was purified by flash chromatography (eluted withDCM/MeOH=30/1) to afford 4-bromo-6-chloro-5-methylpyridazin-3-amine aswhite solid (940 mg, 26% yield). LC-MS: m/z 221.9, 223.9 (M+H)⁺

Step D: N-(4-bromo-6-chloro-5-methylpyridazin-3-yl)-6-ethoxypicolinamide

To a solution of 4-bromo-6-chloro-5-methylpyridazin-3-amine (946 mg,4.25 mmol, 1.0 equiv) in THF (20 mL) was added NaH (60% in mineral oil,510 mg, 12.8 mmol, 3.0 equiv) at 0° C. After the mixture was stirred at0° C. for 1 hour, a solution of 6-ethoxypicolinoyl chloride (946 mg, 5.1mmol, 1.2 equiv) in DCM (10 mL) was added dropwise. The resultingmixture was stirred at room temperature overnight. The reaction mixturewas quenched with NH₄Cl solution (aq., 10 mL) and extracted with DCM (50mL*3). The combined organic layers were washed with brine (20 mL), driedover anhydrous Na₂SO₄ and concentrated in vacuo. The residue purified byflash chromatography on silica gel (eluted with DCM/MeOH=100/3) toafford N-(4-bromo-6-chloro-5-methylpyridazin-3-yl)-6-ethoxypicolinamideas a light yellow solid (700 mg, 44% yield). LC-MS: m/z 371.0, 373.0(M+H)⁺

Step E:N-(6-Chloro-4-((2,6-dimethoxyphenyl)amino)-5-methylpyridazin-3-yl)-6-ethoxypicolinamide

A suspension ofN-(4-bromo-6-chloro-5-methylpyridazin-3-yl)-6-ethoxypicolinamide (600mg, 1.60 mmol, 1.0 equiv), 2,6-dimethoxyaniline (372 mg, 2.40 mmol, 1.5equiv), Pd₂(dba)₃ (150 mg, 0.160 mmol, 0.1 equiv), Xantphos (378 mg,0.640 mmol, 0.4 equiv) and K₂CO₃ (450 mg, 3.20 mmol, 2.0 equiv) in1,4-dioxane (20 mL) was stirred at 130° C. via microwave irradiation for3 hours under N₂ atmosphere. The mixture was filtered through celite andthe filtrate was concentrated in vacuo. The residue was purified byflash chromatography (EtOAc/DCM=1/3) to affordN-(6-chloro-4-((2,6-dimethoxyphenyl)amino)-5-methylpyridazin-3-yl)-6-ethoxypicolinamideas yellow solid (77 mg, 9% yield). LC-MS: m/z 444.1, 446.1 (M+H)⁺

Step F:Chloro-7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-6-methyl-7H-imidazo[4,5-c]pyridazine

A solution ofN-(6-chloro-4-((2,6-dimethoxyphenyl)amino)-5-methylpyridazin-3-yl)-6-ethoxypicolinamide(77.0 mg, 0.170 mmol) in AcOH (5 mL) was stirred at 120° C. viamicrowave irradiation for 2 hours. The mixture was concentrated invacuo, and the residue was purified by pre-TLC (EtOAc/PE=1/1) to affordchloro-7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-6-methyl-7H-imidazo[4,5-c]pyridazineas white solid (15.0 mg, 20% yield). LC-MS: m/z 426.1, 428.1 (M+H)⁺

Step G:N-(7-(2,6-Dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-6-methyl-7H-imidazo[4,5-c]pyridazinyl)methanesulfonamide(Example 139)

A suspension ofchloro-7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-6-methyl-7H-imidazo[4,5-c]pyridazine(15.0 mg, 0.0350 mmol, 1.0 equiv), methanesulfonamide (17.0 mg, 0.180mmol, 6 equiv), CuI (13.0 mg, 0.070 mmol, 2.0 equiv), trans-N,N′-dimethylcyclohexane-1, 2-diamine (10.0 mg, 0.070 mmol, 2.0 equiv) andK₂CO₃ (15 mg, 0.105 mmol, 3 equiv) in DMF (2 mL) was stirred at 140° C.via microwave irradiation for 4 hours under N₂ atmosphere. The reactionwas diluted with water (10 mL) and extracted with EtOAc (10 mL*3). Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by pre-HPLC(eluted with CH₃CN/H₂O=5/95˜90/10 including 0.1% HCOOH) to affordN-(7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-6-methyl-7H-imidazo[4,5-c]pyridazinyl)methanesulfonamideas a yellow solid (4.00 mg, 23% yield).

1H NMR (400 MHz, Chloroform-d) δ: 8.07 (d, J=7.2 Hz, 1H), 7.78-7.64 (m,1H), 7.42 (t, J=8.4 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 6.64 (d, J=8.4 Hz,2H), 3.67 (s, 6H), 3.44 (q, J=7.2 Hz, 2H), 3.09 (s, 3H), 1.78 (s, 3H),1.12 (t, J=7.2 Hz, 3H). LC-MS: m/z 485.0 (M+H)⁺

Step A:N-(5-((Benzyloxy)methyl)-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

To a suspension ofN-(5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide(404 mg, 0.800 mmol, 1.0 equiv), potassium((benzyloxy)methyl)trifluoroborate (456 mg, 2.00 mmol, 2.5 equiv), K₃PO₄(509.6 mg, 2.40 mmol, 3 equiv) in dioxane/water (6 mL/2 mL) was addedPd₂(dba)₃ (146 mg, 0.16 mmol, 0.2 equiv) at room temperature. Theresulting mixture was degassed and re-charged with N₂ for three timesand then stirred at 100° C. for 50 hours under N₂ atmosphere. Thereaction mixture was diluted with water (50 mL), followed by extractionwith EtOAc (50 mL*2). The combined organic layers were dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified byflash chromatography (eluted with DCM/MeOH=120/1˜35/1) to giveN-(5-((benzyloxy)methyl)-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamiideas a yellow solid (70.0 mg, 14.8% yield). LC-MS: m/z 591.0 (M+H)⁺

Step B:N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-5-(hydroxymethyl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide(Example 140)

To a mixture ofN-(5-((benzyloxy)methyl)-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide(100 mg, 0.169 mmol, 1.0 equiv) in DCM (5 mL) were addedtrifluoromethanesulfonic acid (1 mL) and trifluoromethanesulfonicanhydride (0.5 mL) at −78° C. under N₂ atmosphere. The resulting mixturewas stirred at −78° C. for 3.5 hours under N₂ atmosphere. Then themixture was basified to pH=6 with aqueous NaHCO₃ solution (3 mol/L). Themixture was extracted with DCM (20 mL*3). The combined organic layerswere washed with brine (20 mL), dried over Na₂SO₄, filtered andevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel (eluted with DCM/MeOH=50/1˜25/1) to giveN-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-5-(hydroxymethyl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamideas yellow solid (30.0 mg, 36% yield). ¹H NMR (400 MHz, CD₃OD) δ: 7.85(d, J=7.6 Hz, 1H), 7.76 (t, J=8.4 Hz, 1H), 7.44 (t, J=8.4 Hz, 1H), 6.82(d, J=8.4 Hz, 2H), 6.73 (d, J=8.0 Hz, 1H), 4.89 (s, 2H), 3.62 (s, 6H),3.47 (q, J=7.2 Hz, 2H), 3.18 (s, 3H), 1.07 (t, J=7.2 Hz, 3H). LC-MS: m/z501.1 (M+H)⁺

Step C:N-(5-(Difluoromethoxymethyl)-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide(Example 141)

To a mixture ofN-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-5-(hydroxymethyl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide(50.0 mg, 0.100 mmol, 1 equiv), KOAc (98.2 mg, 1.00 mmol, 10 equiv) inDCM/H₂O (8 mL/8 mL) was added (bromodifluoromethyl)trimethylsilane (122mg, 0.600 mmol, 6 equiv) at room temperature under N₂ atmosphere. Theresulting mixture was stirred at room temperature for 5 days under N₂atmosphere. Then the mixture was extracted with DCM (10 mL*2). Thecombined organic layers were washed with brine (10 mL), dried overNa₂SO₄, filtered and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (eluted withDCM/MeOH=50/1˜30/1) and prep-HPLC to giveN-(5-((difluoromethoxy)methyl)-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamideas a yellow solid (2.20 mg, 4% yield). ¹H NMR (400 MHz, Chloroform-d) δ:8.10 (d, J=7.2 Hz, 1H), 7.69 (t, J=8.0 Hz, 1H), 7.45 (s, 1H), 7.37 (t,J=8.4 Hz, 1H), 6.66-6.72 (m, 3H), 6.39 (t, J=73.2 Hz, 1H), 5.26 (s, 2H),3.61 (s, 6H), 3.43 (q, J=7.2 Hz, 2H), 3.25 (s, 3H), 1.07 (t, J=7.2 Hz,3H). LC-MS: m/z 551.1 (M+H)⁺

Example 142:N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(5-methylpyrimidin-2-yl)methanesulfonamide

The title compound was prepared according to Method K, step D, startingfrom6-bromo-5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using (5-methylpyrimidin-2-yl)methanesulfonamide. ¹H NMR (400 MHz,DMSO-d₆) δ: 10.86 (s, 1H), 8.63 (s, 2H), 7.96 (d, J=6.8 Hz, 1H), 7.88(t, J=7.6 Hz, 1H), 7.44 (t, J=8.4 Hz, 1H), 6.78-6.90 (m, 3H), 4.87 (s,2H), 3.51 (s, 6H), 3.39 (q, J=7.2 Hz, 2H), 2.26 (s, 3H), 1.01 (t, J=7.2Hz, 3H). LC-MS: m/z 597.1 (M+H)⁺

Example 143:N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(3-fluorophenyl)methanesulfonamide

The title compound was prepared according to Method K, step D, startingfrom6-bromo-5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazineby using (3-fluorophenyl)methanesulfonamide. ¹H NMR (400 MHz,Chloroform-d) δ: 8.11 (d, J=7.6 Hz, 1H), 7.70 (t, J=7.6 Hz, 1H), 7.42(t, J=8.4 Hz, 1H), 7.26-7.28 (m, 1H), 7.18 (s, 1H), 7.04-7.06 (m, 1H),6.98 (d, J=7.6 Hz, 1H), 6.83 (d, J=9.6 Hz, 1H), 6.72-6.74 (m, 3H), 4.62(s, 2H), 3.64 (s, 6H), 3.43 (q, J=7.2 Hz, 2H), 1.08 (t, J=7.2 Hz, 3H).LC-MS: m/z 599.1 (M+H)

Step A: 5-Chloro-2-amino(bis-carbamate)pyrimidine

To a solution of 2-chloropyrimidin-5-amine (5.00 g, 39.0 mmol, 1.0equiv) in THF were added Boc₂O (17.9 g, 82.0 mmol, 2.1 equiv) and DMAP(476 mg, 3.90 mmol, 0.10 equiv). The mixture was stirred at roomtemperature for 3 h. TLC showed the starting material was consumedcompletely. The mixture was concentrated and purified by silica gelcolumn chromatography (PE/EA=15/1) to give5-chloro-2-amino(bis-carbamate)pyrimidine as a white solid (11.6 g, 91%yield). LC-MS: m/z 329.8 (M+H)⁺

Step B: Methyl 5-((tert-butoxycarbonyl)amino)pyrimidine-2-carboxylate

To a solution of 5-chloro-2-amino(bis-carbamate)pyrimidine (10.6 g, 32.0mmol, 1.0 equiv) in MeOH (200 ml) and DMF (40 ml) were added TEA (9.72g, 96.0 mol, 3.0 equiv) and Pd(dppf)Cl₂ (3.51 g, 5.00 mmol, 0.16 equiv).The suspension was degassed and purged with CO several times. Themixture was stirred under CO (3 MPa) at 120° C. overnight. The reactionmixture was cooled to room temperature and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/EA=2/1) togive methyl 5-((tert-butoxycarbonyl)amino)pyrimidine-2-carboxylate as ayellow solid (5.32 g, 65% yield). LC-MS: m/z 254.0 (M+H)⁺

Step C: tert-Butyl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate

To a solution of methyl5-((tert-butoxycarbonyl)amino)pyrimidine-2-carboxylate (5.32 g, 21.0mmol, 1.0 equiv) in MeOH (50 mL) was added NaBH₄ (954 mg, 25.2 mmol, 1.2equiv) at 0° C. The mixture was stirred at room temperature for 5 h.Then the mixture was diluted with H₂O (50 mL) and extracted with DCM (50ml*3). The combined DCM layers were washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated. The crude residue waspurified by silica gel column chromatography (DCM/MeOH=40/1) to givetert-butyl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate as a yellow solid(2.90 g, 61% yield). LC-MS: m/z 226.01 (M+H)⁺

Step D: tert-Butyl(2-(benzo[d]thiazol-2-ylthio)methyl)pyrimidin-5-yl)carbamate

To a solution of tert-butyl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate(2.93 g, 13.0 mmol, 1.0 equiv), benzo[d]thiazole-2-thiol (2.61 g, 15.6mmol, 1.2 equiv) and PPh₃ (4.10 g, 15.6 mmol, 1.2 equiv) in THF wasadded DEAD (2.72 g, 15.6 mmol, 1.2 equiv) at 0° C. The mixture wasstirred at room temperature for 16 hours. The mixture was concentratedin vacuo and purified by silica gel column chromatography (PE/EA=5/1) togive tert-butyl(2-((benzo[d]thiazol-2-ylthio)methyl)pyrimidin-5-yl)carbamate as ayellow solid (4.50 g, 92% yield). LC-MS: m/z 374.9 (M+H)⁺

Step E: tert-Butyl(2-((benzo[d]thiazol-2-ylsulfonyl)methyl)pyrimidin-5-yl)carbamate

To a solution of tert-butyl(2-((benzo[d]thiazol-2-ylthio)methyl)pyrimidin-5-yl)carbamate (3.00 g,8.02 mmol, 1.0 equiv) in DCM (60 mL) was added m-CPBA (85% purity) (1.95g, 9.62 mmol, 1.20 equiv). The mixture was stirred at room temperaturefor 16 hours and quenched with 1 N Na₂SO₃ aqueous solution. The organicphase was separated, washed with saturated Na₂CO₃ aqueous solution andbrine. The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash chromatography(eluted with PE/EtOAc=3/1) to afford tert-butyl(2-((benzo[d]thiazol-2-ylsulfonyl)methyl)pyrimidin-5-yl)carbamate as awhite solid (1.39 g, 43% yield). LC-MS: m/z 407.0 (M+H)⁺

Step F: tert-Butyl (2-(sulfamoylmethyl)pyrimidin-5-yl)carbamate

To a solution of tert-butyl(2-((benzo[d]thiazol-2-ylsulfonyl)methyl)pyrimidin-5-yl)carbamate (1.39g, 3.42 mmol, 1.0 equiv) in MeOH (30 mL) was added K₂CO₃ (2.36 g, 17.1mmol, 5.0 equiv). After the mixture was stirred at room temperature for30 mins, 20 mL H₂O and NH₂OSO₃H (929 mg, 8.21 mmol, 2.4 equiv) in H₂O(10 mL) were added. The resulting mixture was stirred at roomtemperature for 16 hours. The mixture was concentrated and the residuewas purified by flash chromatography (DCM/MeOH=20/1) to afford the titlecompound tert-butyl (2-(sulfamoylmethyl)pyrimidin-5-yl)carbamate as awhite solid (310 mg, 31% yield). ¹H NMR (400 MHz, DMSO-d6) δ: 9.83 (s,1H), 8.85 (s, 2H), 6.92 (s, 2H), 4.48 (s, 2H), 1.49 (s, 9H).

Step G:1-(5-Aminopyrimidin-2-yl)-N-(7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazinyl)methanesulfonamide

A suspension of tert-butyl (2-(sulfamoylmethyl)pyrimidin-5-yl)carbamate(166 mg, 0.576 mmol, 1.2 equiv),chloro-7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazine(200 mg, 0.490 mmol, 1.0 equiv),trans-N,N′-dimethylcyclohexane-1,2-diamine (70.0 mg, 0.490 mmol, 1.0equiv), CuI (93.0 mg, 0.490 mmol, 1.0 equiv), NaI (74.0 mg, 0.490 mmol,1.0 equiv) and K₂CO₃ (135 mg, 0.980 mmol, 2.0 equiv) in DMF (4 mL) wasstirred at 140° C. via microwave irradiation for 2 hours under N₂atmosphere. The reaction mixture was filtered and filtrate wasconcentrated in vacuo. The residue was purified by prep-HPLC (elutedwith CH₃CN/H₂O=5/95˜95/5 including 0.1% HCOOH) to give1-(5-aminopyrimidin-2-yl)-N-(7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazinyl)methanesulfonamideas a yellow solid (70.0 mg, 25% yield). LC-MS: m/z 564.3 (M+H)+

Step H:1(5-Chloropyrimidin-2-yl)-N-(7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazinyl)methanesulfonamide(Example 144)

A suspension of1-(5-aminopyrimidin-2-yl)-N-(7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazinyl)methanesulfonamide(80.0 mg, 0.140 mmol, 1.0 equiv), CuCl (28.0 mg, 0.280 mmol, 2.0 equiv),CuCl₂ (56.0 mg, 0.420 mmol, 3.0 equiv) in DCM (4 mL) was stirred at 0°C. for 10 mins. tert-Butyl nitrite (43.0 mg, 0.420 mmol, 3.0 equiv) wasadded. The mixture was stirred at room temperature for 4 h. The reactionmixture was filtered and filtrate was concentrated in vacuo. The residuewas purified by prep-TLC (DCM/MeOH=30/1) to afford the crude product,which was further purified with prep-HPLC (eluted withCH₃CN/H₂O=5/95˜95/5 including 0.1% HCOOH) to give1-(5-chloropyrimidin-2-yl)-N-(7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazinyl)methanesulfonamideas a yellow solid (3.00 mg, 4% yield). ¹H NMR (400 MHz, DMSO-d₆) δ: 8.83(s, 2H), 8.00 (d, J=7.2 Hz, 1H), 7.92 (t, J=8.4 Hz, 1H), 7.51 (t, J=8.4Hz, 1H), 6.80-7.03 (m, 4H), 4.70 (s, 2H), 3.61 (s, 6H), 3.37-3.42 (m,2H), 1.03 (t, J=7.2 Hz, 3H). LC-MS: m/z 583.2 (M+H)+

Step A: N-(tert-Butoxycarbonyl)-N-(6-chloropyrazin-2-yl) tert-butylcarbamate

To a solution of 6-chloropyrazin-2-amine (20.0 g 154 mmol, 1.0 equiv)and (Boc)₂O (101 g, 462 mmol, 3.0 equiv) in DCM (250 mL) was added DMAP(1.90 g, 15.4 mmol, 0.10 equiv). The mixture was stirred at roomtemperature for 3 hours. The solvent was evaporated in vacuum and theresidue was purified by silica gel column chromatography (eluted withPE/EtOAc=95/5) to afford the title compoundN-(tert-butoxycarbonyl)-N-(6-chloropyrazin-2-yl) tert-butyl carbamate asa white solid (49.8 g, 98% yield). LC-MS: m/z 330.1 (M+H)⁺

Step B: N-(tert-Butoxycarbonyl)-N-(6-acetylamidopyrazin-2-yl) tert-butylcarbamate

A suspension of N-(tert-butoxycarbonyl)-N-(6-chloropyrazin-2-yl)tert-butyl carbamate (15.0 g, 45.6 mmol, 1.0 equiv), acetamide (5.40 g,91.2 mmol, 2.0 equiv), Pd(OAc)₂ (2.10 g, 9.12 mmol, 0.20 equiv),Xantphos (10.5 g, 18.2 mmol, 0.40 equiv) and K₂CO₃ (12.6 g, 91.2 mmol,2.0 equiv) in 1,4-dioxane (250 mL) was refluxed under N₂ for 5 hours.The reaction mixture was poured into water (500 mL) and extracted withDCM (500 mL*3). The extracts were dried over anhydrous Na₂SO₄ andevaporated to dryness. The residue was purified by silica gel columnchromatography (eluted with PE/EtOAc=3/1) to afford the title compoundN-(tert-butoxycarbonyl)-N-(6-acetylamidopyrazin-2-yl) tert-butylcarbamate as a yellow solid (14.0 g, 87% yield). LC-MS: m/z 353.2 (M+H)⁺

Step C: N-(6-Aminopyrazin-2-yl)acetamide

To a solution of N-(tert-butoxycarbonyl)-N-(6-acetylamidopyrazin-2-yl)tert-butyl carbamate (14.0 g, 39.8 mmol, 1.0 equiv) in DCM (200 mL) wasadded TFA (40 mL). The mixture was stirred at room temperature for 1hour. Then the mixture was adjusted to pH 8 with Na₂CO₃ aqueous solutionand the resulting mixture was concentrated under vacuum. The residue waspurified by silica gel column chromatography (eluted with DCM/MeOH=20/1)to afford the title compound N-(6-aminopyrazin-2-yl)acetamide as ayellow solid (5.00 g, 83% yield). LC-MS: m/z 153.1 (M+H)⁺

Step D: N-(6-Amino-3,5-dibromopyrazin-2-yl)acetamide

To a solution of N-(6-aminopyrazin-2-yl)acetamide (5.00 g, 32.9 mmol,1.0 equiv) in ACN (400 mL) was added NBS (12.9 g, 72.4 mmol, 2.2 equiv)under N₂. The resulting mixture was stirred at room temperature for 4hours. The solvent was evaporated and the residue was washed by H₂O for3 times. The resulting mixture was purified by silica gel columnchromatography (eluted with DCM/MeOH=30/1) to afford the title compoundN-(6-amino-3,5-dibromopyrazin-2-yl)acetamide as a light yellow solid(7.70 g, 76% yield). LC-MS: m/z 308.9, 310.9, 312.9 (M+H)⁺. ¹H NMR (400MHz, DMSO-d₆) δ: 10.01 (s, 1H), 6.99 (br. s, 2H), 2.03 (s, 3H).

Step E: N-(6-Acetamido-3,5-dibromopyrazin-2-yl)-6-ethoxypicolinamide

To a solution of N-(6-amino-3,5-dibromopyrazin-2-yl)acetamide (5.00 g,16.1 mmol, 1.0 equiv) in THF (200 mL) was added NaH (60% in mineral oil,3.40 g, 48.4 mmol, 3.0 equiv) at 0° C. The mixture was warmed up to roomtemperature and kept stirring for 1 hour. 6-Ethoxypicolinoyl chloride(3.60 g, 19.4 mmol, 1.20 equiv) in DCM (10 mL) was added dropwise at 0°C. The mixture was stirred at room temperature for another 1 hour. Thenthe mixture was adjusted to pH7 with HCl aqueous solution and thesolvent was evaporated under vacuum. The residue was purified by silicagel column chromatography (eluted with DCM/EtOAc=4/1) to afford thetitle compoundN-(6-acetamido-3,5-dibromopyrazin-2-yl)-6-ethoxypicolinamide as a paleyellow solid (3.20 g, 43% yield). LC-MS: m/z 457.9, 459.9, 461.9 (M+H)⁺

Step F: N-(6-Amino-3,5-dibromopyrazin-2-yl)-6-ethoxypicolinamide

A solution ofN-(6-acetamido-3,5-dibromopyrazin-2-yl)-6-ethoxypicolinamide (3.20 g,6.97 mmol, 1.0 equiv) in HCl (15% aqueous, 60 mL) and MeOH (100 mL) wasstirred at 50° C. for 5 hours. Then the mixture was adjusted to pH8 withNa₂CO₃ aqueous solution and the mixture was concentrated under vacuum.The residue was purified by silica gel column chromatography (elutedwith DCM/MeOH=30/1) to afford the title compoundN-(6-amino-3,5-dibromopyrazin-2-yl)-6-ethoxypicolinamide as a yellowsolid (2.00 g, 67% yield). LC-MS: m/z 415.9, 417.9, 419.9 (M+H)⁺

Step G:N-(6-Bis(tert-butoxycarbonyl)amino-3,5-dibromopyrazin-2-yl)-6-ethoxypicolinamide

A suspension of N-(6-amino-3,5-dibromopyrazin-2-yl)-6-ethoxypicolinamide(2.00 g, 4.70 mmol, 1.0 equiv) and (Boc)₂O (2.00 g, 9.40 mmol, 2.0equiv) in DCM (100 mL) was added Et₃N (1.50 g, 14.1 mmol, 3.0 equiv) andDMAP (57.3 mg, 0.470 mmol, 0.10 equiv). The mixture was stirred at roomtemperature for 3 hours. Then the mixture was concentrated in vacuo andthe residue was purified by silica gel column chromatography (elutedwith PE/EtOAc=4/1) to afford the title compoundN-(6-bis(tert-butoxycarbonyl)amino-3,5-dibromopyrazin-2-yl)-6-ethoxypicolinamideas a white solid (1.10 g, 39% yield). LC-MS: m/z 616.0, 618.0, 620.0(M+H)⁺

Step H:N-(6-Bis(tert-butoxycarbonyl)amino-5-bromo-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide

A suspension ofN-(6-bis(tert-butoxycarbonyl)amino-3,5-dibromopyrazin-2-yl)-6-ethoxypicolinamide(980 mg, 1.60 mmol, 1.0 equiv), 2,6-dimethoxyaniline (487 mg, 3.20 mmol,2.0 equiv), Pd₂(dba)₃ (293 mg, 0.300 mmol, 0.20 equiv), Xantphos (371mg, 0.600 mmol, 0.40 equiv) and K₂CO₃ (657 mg, 4.80 mmol, 3.0 equiv) in1,4-dioxane (12 mL) was stirred at 120° C. via microwave irradiationunder N₂ for 2 hours. Then the mixture was concentrated in vacuo and theresidue was purified by silica gel column chromatography (eluted withPE/EtOAc=5/1) to afford the title compoundN-(6-bis(tert-butoxycarbonyl)amino-5-bromo-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamideas a yellow solid (750 mg, 69% yield).

LC-MS: m/z 689.2, 691.2 (M+H)⁺

Step I:6-Bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-amine

A solution ofN-(6-bis(tert-butoxycarbonyl)amino-5-bromo-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide(750 mg, 1.10 mmol, 1.0 equiv) in AcOH (10 mL) was stirred at 145° C.via microwave irradiation for 1 hour. Then the mixture was concentratedin vacuo and the residue was purified by prep-HPLC (eluted withCH₃CN/H₂O=5/95˜95/5 including 0.1% TFA) to afford the title compound6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-amineas a yellow solid (200 mg, 39% yield). LC-MS: m/z 471.1, 473.1 (M+H)⁺

Step J:N-(tert-Butoxycarbonyl)-N-(6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)tert-butyl carbamate

A solution of6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-amine(200 mg, 0.400 mmol, 1.0 equiv) and (Boc)₂O (463 mg, 2.00 mmol, 5.0equiv) in 1,4-dioxane (10 mL) was added Et₃N (139 mg, 1.20 mmol, 3.0equiv) and DMAP (5.30 mg, 0.0400 mmol, 0.10 equiv). The mixture wasstirred at 80° C. overnight. Then the reaction mixture was concentratedin vacuo and the residue was purified by silica gel columnchromatography (eluted with PE/EtOAc=2/1) to afford the title compoundN-(tert-butoxycarbonyl)-N-(6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)tert-butyl carbamate as a yellow solid (200 mg, 71% yield). LC-MS: m/z671.2, 673.2 (M+H)⁺

Step K:N-(tert-Butoxycarbonyl)-N-(1-(2,6-dimethoxyphenyl-2-(6-ethoxypyridin-2-yl)-6-(methylsulfonamido)-1H-imidazo[4,5-b]pyrazin-5-yl)tert-butyl carbamate

A suspension ofN-(tert-butoxycarbonyl)-N-(6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)tert-butyl carbamate (200 mg, 0.300 mmol, 1.0 equiv), methanesulfonamide(143 mg, 1.50 mmol, 5.0 equiv), N¹,N²-dimethylcyclohexane-1,2-diamine(85.0 mg, 0.600 mmol, 2.0 equiv), CuI (114 mg, 0.600 mmol, 2.0 equiv)and K₂CO₃ (124 mg, 0.900 mmol, 3.0 equiv) in DMF (5 mL) was stirred at120° C. via microwave irradiation under N₂ for 5 hours. The mixture waspoured into a mixture of water (50 mL) and HCOOH (2 mL), and extractedwith DCM (50 mL*3). The combined organic layers were dried over Na₂SO₄and concentrated under vacuum. The residue was purified by prep-HPLC(eluted with CH₃CN/H₂O=5/95˜95/5 including 0.1% HCOOH) to afford thetitle compoundN-(tert-butoxycarbonyl)-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-6-(methylsulfonamido)-1H-imidazo[4,5-b]pyrazin-5-yl)tert-butyl carbamate as a yellow solid (48.0 mg, 23% yield). LC-MS: m/z686.3 (M+H)⁺

Step L:N-(5-Amino-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide(Example 145)

A solution ofN-(tert-butoxycarbonyl)-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-6-(methylsulfonamido)-1H-imidazo[4,5-b]pyrazin-5-yl)tert-butyl carbamate (48.0 mg, 0.0700 mmol, 1.0 equiv) in HCOOH (10 mL)was stirred at room temperature for 1 hour. The mixture was concentratedunder vacuum and the residue was purified by prep-HPLC (eluted withCH₃CN/H₂O=5/95˜95/5 including 0.1% TFA) to afford the title compoundN-(5-amino-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamideas a yellow solid (27.0 mg, 80% yield). LC-MS: m/z 486.2 (M+H)⁺. ¹H NMR(400 MHz, Chloroform-d) δ: 8.05 (d, J=7.6 Hz, 1H), 7.69 (t, J=8.0 Hz,1H), 7.41 (t, J=8.4 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.69 (d, J=8.4 Hz,2H), 3.65 (s, 6H), 3.48 (q, J=7.2 Hz, 2H), 3.15 (s, 3H), 1.09 (t, J=7.2Hz, 3H).

Step M:N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-5-fluoro-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide(Example 146)

To a mixture ofN-(5-amino-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide(27.0 mg, 0.0600 mmol, 1.0 equiv) in acetonitrile (2 mL) and HBF₄ (48%aqueous solution, 0.800 mL) was added NaNO₂ (4.70 mg, 0.0690 mmol, 1.15equiv) at 0° C. After stirred for 1 hour at room temperature, thereaction mixture was poured into water (50 mL) and extracted with DCM(50 mL). The extracts were evaporated to dryness and the residue waspurified by prep-HPLC (eluted with CH₃CN/H₂O=5/95˜95/5 including 0.1%HCOOH) to afford the title compoundN-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-5-fluoro-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamideas a yellow solid (5.00 mg, 20% yield). LC-MS: m/z 489.1 (M+H)⁺. ¹H NMR(400 MHz, Chloroform-d) δ: 8.07 (dd, J=7.6, 0.8 Hz, 1H), 7.68 (t, J=8.0Hz, 1H), 7.37 (t, J=8.4 Hz, 1H), 7.17 (s, 1H), 6.65-6.72 (m, 3H), 3.62(s, 6H), 3.43 (q, J=7.2 Hz, 2H), 3.28 (s, 3H), 1.07 (t, J=7.2 Hz, 3H).

Methods for Evaluating Compounds:

Activation of APJ receptor is known to inhibit forskolin-stimulatedcyclic AMP (cAMP) production in cells in a pertussis toxin-sensitivemanner which indicates primary coupling to the G_(αI) subunit of the Gprotein heterotrimeric complex. In addition to signaling through Gprotein and inhibition of cAMP, APJ receptor activation also results inβ-arrestin recruitment, receptor internalization and activation ofextracellular-regulated kinases (ERKs). Evidence suggests signalingthrough Gi induced cAMP inhibition elicits the desired inotropic andvasodilatory pharmacological response whereas arrestin recruitmentresults in receptor internalization, downregulation and ultimatelycardiac hypertrophy.

In order to optimize functional activity directed toward Gi coupling weutilized a CHO-K1 cell line developed by DiscoverX stably expressing theAPJ Receptor. Cells expressing APJR receptor were plated in a 384-wellmicrotiter plates and incubated overnight at 37° C. with 5% CO₂ to allowthe cells to attach and grow. Media was then aspirated from the cellsand replaced with 15 uL 2:1 Hanks Balanced Salt Solution (HBSS)/10 mMHepes:cAMP XS+ Ab reagent. Five microliters (5 uL) of previouslygenerated compound sample stocks at 4× final concentration in assaybuffer containing 4× EC80 forskolin were then added to the cells andallowed to incubate at 37° C. for 30 minutes.

After incubation the assay signal was generated using a technologytermed enzyme fragment complementation (EFC). In EFC the enzymeB-galactosidase is split into two complementary portions (EA and ED).The fragment ED is fused to cAMP and in the assay format competes withendogenous cAMP for binding to a cAMP specific antibody. Activated B-Galis formed when exogenous EA fragment binds to free ED-cAMP (not bound tocAMP specific antibody). Activated enzyme levels are detected throughconversion of B-gal chemiluminescent substrate which generates adetectable luminescence signal and read on standard microtiter plate.

The methodology for detection of cAMP using EFC requires incubation with20 uL of cAMP XS+ ED/CL lysis cocktail for one hour followed byincubation with 20 uL cAMP XS+ EA reagent for three hours at roomtemperature. Microplates were read following signal generation with aPerkinElmer Envision instrument utilizing chemiluminescent signaldetection.

Compound activity was analyzed using CBIS data analysis suite(ChemInnovation, CA). Percentage activity was calculated using thefollowing formula:% Activity=100%×(1−(mean RLU of test sample−mean RLU of Maxcontrol)/(mean RLU of vehicle control−mean RLU of Max control))

The biological activity of the exemplified compounds of this inventiondetermined by the assay described above is shown in Table 1. The APJcAMP EC50 potency ranges are as follows: A: EC50<1 nM; B: 1≤EC50<100 nM;and C: 100≤EC50<10,000 nM.

TABLE 1 Example compounds and their potency range Example Potency #Structure IUPAC Name Range 1

6-bromo-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine C 2

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6- yl)methanesulfonamide B 3

N-(1-(2,6 dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1Himidazo[4,5-b]pyrazin- 6-yl)-1- phenylmethanesulfonamide B 4

1-cyclopropyl-N-(1- (2,6-dimethoxyphenyl)- 2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5- b]pyrazin-6- yl)methanesulfonamide B 5

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6- yl)benzenesulfonamide A 6

1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-6-(phenylethynyl)-1H- imidazo[4,5-b]pyrazine C 7

1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-6- phenethyl-1H-imidazo[4,5-b]pyrazine B 8

N-Benzyl-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine- 6-carboxamide C 9

1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-N-methyl-1H-imidazo[4,5- b]pyrazin-6-amine B 10

1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-amine B 11

N,N-dibenzyl-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-amine B 12

1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)- N,N-dimethyl-1H-imidazo[4,5-b]pyrazin- 6-amine C 13

N-benzyl-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-amine B 14

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-2-phenylacetamide B 15

5-chloro-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine C 16

1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 5-amine B 17

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 5-yl)-2-phenylacetamide B 18

1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine C 19

N-(5-(2,6- dimethoxyphenyl)-6-(6- ethoxypyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazin-3- yl)methanesulfonamide C 20

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyridin-6- yl)methanesulfonamide B 21

N-(5-(2,6- dimethoxyphenyl)-6-(6- ethoxypyridin-2-yl)-5 H-imidazo[4,5-c]pyridazin- 3- yl)methanesulfonamide B 22

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6- yl)cyclopropanesulfon- amide B 23

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)pyridine-2- sulfonamide A 24

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)pyridine-3- sulfonamide B 25

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)pyridine-4- sulfonamide B 26

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-1-(pyridin-3- yl)methanesulfonamide B 27

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-1-(pyridin-2- yl)methanesulfonamide B 28

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-1-(pyrimidin-2- yl)methanesulfonamide A 29

2-cyclopropyl-N-(1- (2,6-dimethoxyphenyl)- 2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5- b]pyrazin-6- yl)ethanesulfonamide A 30

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)oxetane-3- sulfonamide B 31

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6- yl)cyclobutanesulfonamide B 32

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-N- methylmethanesulfonamide C 33

cis-N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-3- hydroxycyclobutane-1- sulfonamide B 34

trans-N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-3- hydroxycyclobutane-1- sulfonamide B 35

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-1-(pyrimidin-5- yl)methanesulfonamide B 36

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)tetrahydro-2H- pyran-4-sulfonamide B 37

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)morpholine-4- sulfonamide A 38

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-1-(piperidin-4- yl)methanesulfonamide B 39

trans-N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-4- hydroxycyclohexane-1- sulfonamide A 40

cis-N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-4- hydroxycyclohexane-1- sulfonamide B 41

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)pyrimidine-2- sulfonamide B 42

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-4- hydroxypiperidine-1- sulfonamide B 43

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 5- yl)methanesulfonamide B 44

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 5- yl)methanesulfonamide A 45

1-cyclopropyl-N-(1- (2,6-dimethoxyphenyl)- 2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5- b]pyrazin-5- yl)methanesulfonamide A 46

1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-N-(4-methoxybenzyl)-1H- imidazo[4,5-b]pyrazin- 5-amine A 47

2-(6-ethoxypyridin-2- yl)-1-(2-methoxy-6- (trifluoromethyl)phenyl)-1H-imidazo[4,5- b]pyrazin-6-ol C 48

N-(2-(6-ethoxypyridin- 2-yl)-1-(2-methoxy-6- (trifluoromethyl)phenyl)-1H-imidazo[4,5- b]pyrazin-6- yl)methanesulfonamide B 49

N-(2-(6-ethoxypyridin- 2-yl)-1-(3- methoxypyridin-2-yl)- 1H-imidazo[4,5-b]pyrazin-6- yl)methanesulfonamide C 50

N-(benzylsulfonyl)-4-(2- fluoro-6- methoxyphenyl)-5-(6-methoxypyridin-2-yl)- 4H-1,2,4-triazole-3- carboxamide B 51

N-(1-(2,6- dimethoxyphenyl)-2-(6- methoxypyridin-2-yl)- 1H-imidazo[4,5-b]pyrazin-6- yl)methanesulfonamide B 52

N-(1-(2,6- dimethoxyphenyl)-2-(6- methoxypyridin-2-yl)- 1H-imidazo[4,5-b]pyrazin-6-yl)pyridine- 2-sulfonamide B 53

N-(1-(2,6- dimethoxyphenyl)-2-(6- methoxypyridin-2-yl)- 1H-imidazo[4,5-b]pyrazin-6- yl)pyrimidine-2- sulfonamide B 54

N-(2-(6- cyclopropoxypyridin-2- yl)-1-(2,6- dimethoxyphenyl)-1H-imidazo[4,5-b]pyrazin- 6- yl)methanesulfonamide B 55

N-(1-(2,6- dimethoxyphenyl)-2-(6- (trifluoroethoxy)pyridin-2-yl)-1H-imidazo[4,5- b]pyrazin-6- yl)methanesulfonamide B 56

N-(1-(2,6- dimethoxyphenyl)-2-(6- (trifluoromethoxy)pyridin-2-yl)-1H-imidazo[4,5- b]pyrazin-6- yl)methanesulfonamide C 57

N-(1-(2,6- dimethoxyphenyl)-2- (ethoxymethyl)-1H- imidazo[4,5-b]pyrazin-6- yl)benzenesulfonamide C 58

N-(2-(6-ethoxypyridin- 2-yl)-1-(pentan-3-yl)- 1H-imidazo[4,5-b]pyrazin-6- yl)methanesulfonamide B 59

N-(2-(6-ethoxypyridin- 2-yl)-1-isopropyl-1H- imidazo[4,5-b]pyrazin- 6-yl)methanesulfonamide C 60

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-3-hydroxy-3- methylbutane-1- sulfonamide B61

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-1-(1- hydroxycyclopropyl)methanesulfonamide B 62

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 5-yl)-1-(1- hydroxycyclopropyl)methanesulfonamide B 63

N-(3-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-3H-imidazo[4,5-b]pyridin-5- yl)methanesulfonamide B 64

N-(5-chloro-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6- yl)methanesulfonamide B 65

N-(5- (cyclopropylmethyl)-1- (2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2- yl)-1H-imidazo[4,5- b]pyrazin-6-yl)methanesulfonamide A 66

N-(5-(2- cyclopropylethyl)-1- (2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2- yl)-1H-imidazo[4,5- b]pyrazin-6-yl)methanesulfonamide A 67

N-(cyclopropylmethyl)- 1-(2,6- dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H- imidazo[4,5-b]pyrazin- 6-amine B 68

N-(1-(2,4- dimethoxypyridin-3-yl)- 2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5- b]pyrazin-6- yl)methanesulfonamide B 69

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-1-(pyrazin-2- yl)methanesulfonamide B 70

N-(1-(2,6- Dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-2-hydroxy-2- methylpropane-1- sulfonamide B71

(S)-N-(1-(2,6- Dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-1-(1-methyl-2- oxopiperidin-4-yl)methanesulfonamide A 72

(R)-N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-1-(1-methyl-2- oxopiperidin-4-yl)methanesulfonamide A 73

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)pyrrolidine-1- sulfonamide B 74

N-(1-(2,6- Dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)piperazine-1- sulfonamide B 75

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)piperidine-1- sulfonamide A 76

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-N′,N′- dimethylsulfamide B 77

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-N′-methyl-N′- cyclopropylsulfamide A 78

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-1-(5-fluoropyridin- 2-yl)methanesulfonamide A 79

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-1-(5- fluoropyrimidin-2-yl)methanesulfonamide A 80

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-1-(5- methylpyrimidin-2-yl)methanesulfonamide A 81

trans-N-(1-(2,6- Dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-1-((1r,3r)-3- hydroxy-3-methylcyclobutyl)methane- sulfonamide B 82

N-(1-(2,6- Dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)but-2-yne-1- sulfonamide B 83

N-(1-(2,6- Dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-1-(5- methylpyridin-2-yl)methanesulfonamide A 84

N-(1-(2,4- Dimethoxypyridin-3-yl)- 2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5- b]pyrazin-6- yl)methanesulfonamide B 85

N-(1-(2,4- Dimethoxypyridin-3-yl)- 2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5- b]pyrazin-6- yl)methanesulfonamide] C 86

N-(1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-5-ethyl-1H-imidazo[4,5- b]pyrazin-6- yl)methanesulfonamide B 87

N-(1-(2,6- Dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-5-methyl-1H-imidazo[4,5- b]pyrazin-6- yl)methanesulfonamide B 88

N-(5- (Cyclobutylmethyl)-1- (2,6-dimethoxyphenyl)- 2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5- b]pyrazin-6- yl)methanesulfonamide A 89

N-(5-Cyclopropoxy-1- (2,6-dimethoxyphenyl)- 2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5- b]pyrazin-6- yl)methanesulfonamide C 90

N-(1-(2,6- Dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 5-yl)morpholine-4- sulfonamide A 91

N-(1-(2,6- Dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 5-yl)-1-(5- methylpyrimidin-2-yl)methanesulfonamide A 92

N-(1-(2,6- Dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 5- yl)cyclopropanesulfon- amide B 93

N-(1-(2,6- Dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 5-yl)-1-(3- hydroxyazetidin-3-yl)methanesulfonamide A 94

N-(5-Chloro-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-1-(3-fluoropyridin- 2-yl)methanesulfonamide B 95

N-(5-Chloro-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-1-(pyridin-2- yl)methanesulfonamide B 96

N-(5-Chloro-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-1-(5-fluoropyridin- 2-yl)methanesulfonamide A 97

N-(5-Chloro-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6- yl)cyclopropanesulfon- amide B 98

N-(5-Chloro-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)morpholine-4- sulfonamide B 99

N-(5-Chloro-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-5-fluoropyridine-2- sulfonamide B 100

N-(5-Chloro-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-1-(2-fluoro-4- methylphenyl)methane-sulfonamide B 101

N-(5-Chloro-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-5-methylpyridine- 2-sulfonamide A 102

N-(5-Chloro-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)pyridine-2- sulfonamide B 103

N-(5-Chloro-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-4- (fluoromethyl)benzene- sulfonamide A 104

N-(5-Chloro-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)pyridine-3- sulfonamide B 105

N-(5-Chloro-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-1-(5- fluoropyrimidin-2-yl)methanesulfonamide A 106

N-(5-Chloro-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-4- (difluoromethyl)benzene- sulfonamide B107

N-(5-Chloro-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-1-(3-fluoro-4- methylphenyl)methane-sulfonamide A 108

N-(5-Chloro-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-1-(4- fluorophenyl)methane- sulfonamide A109

N-(5-Chloro-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-1-(pyrimidin-2- yl)methanesulfonamide B 110

N-(5-Chloro-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)but-2-yne-1- sulfonamide A 111

N-(5-Chloro-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)tetrahydro-2H- pyran-4-sulfonamide B 112

N-(5-Chloro-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-N′-methyl-N′- cyclopropylsulfamide A 113

N-(5-Chloro-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-1-(1- hydroxycyclopropyl)methanesulfonamide(ANPA- 0003489) B 114

N-(5-Chloro-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-1-(5- methylpyridin-2-yl)methanesulfonamide B 115

N-(5-Chloro-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-1-((1r,3r)-3- hydroxy-3-methylcyclobutyl)methane- sulfonamide A 116

N-(5-Chloro-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-4- hydroxypiperidine-1- sulfonamide B 117

N-(5-Chloro-1-(3,5- dimethoxypyridin-4-yl)- 2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5- b]pyrazin-6- yl)methanesulfonamide B 118

N-(5-Chloro-1-(3,5- dimethoxypyridin-4-yl)- 2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5- b]pyrazin-6- yl)cyclopropanesulfon- amide B 119

N-(7-(2,6- Dimethoxyphenyl)-8-(6- ethoxypyridin-2-yl)-7H- imidazo[4,5-c]pyridazinyl)cyclo- propanesulfonamide B 120

N-(7-(2,6- Dimethoxyphenyl)-8-(6- ethoxypyridin-2-yl)-7H- imidazo[4,5-c]pyridazinyl)-5- fluoropyridine-2- sulfonamide A 121

N-(7-(2,6- Dimethoxyphenyl)-8-(6- ethoxypyridin-2-yl)-7H- imidazo[4,5-c]pyridazinyl)morpholine- 4-sulfonamide B 122

N-(7-(2,6- Dimethoxyphenyl)-8-(6- ethoxypyridin-2-yl)-7H- imidazo[4,5-c]pyridazinyl)-1-(4- fluorophenyl)methane- sulfonamide A 123

1-(5-Chloropyridin-2- yl)-N-(7-(2,6- dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H- imidazo[4,5- c]pyridazinyl)methane- sulfonamideA 124

N-(7-(2,6- Dimethoxyphenyl)-8-(6- ethoxypyridin-2-yl)-7H- imidazo[4,5-c]pyridazinyl)-1-(5- methylpyridin-2- yl)methanesulfonamide A 125

N-(7-(2,6- Dimethoxyphenyl)-8-(6- ethoxypyridin-2-yl)-7H- imidazo[4,5-c]pyridazinyl)-1-(5- fluoropyridin-2- yl)methanesulfonamide A 126

N-(7-(2,6- Dimethoxyphenyl)-8-(6- ethoxypyridin-2-yl)-7H- imidazo[4,5-c]pyridazinyl)-1-(5- methylpyrimidin-2- yl)methanesulfonamide A 127

N-(5-(2,6- Dimethoxyphenyl)-6-(6- ethoxypyridin-2-yl)-5H-imidazo[4,5-c]pyridazin- 3-yl)-1-(pyrimidin-2- yl)methanesulfonamide A128

N-(5-(2,6- Dimethoxyphenyl)-6-(6- ethoxypyridin-2-yl)-5H-imidazo[4,5-c]pyridazin- 3-yl)-1-(3-hydroxy-3- methylcyclobutyl)methane-sulfonamide A 129

N-(7-(2,6- Dimethoxyphenyl)-8-(6- ethoxypyridin-2-yl)-7H- imidazo[4,5-c]pyridazinyl)-1-(5- hydroxypyrimidin-2- yl)methanesulfonamide B 130

N-(7-(2,6- Dimethoxyphenyl)-8-(5- methylfuran-2-yl)-7H- imidazo[4,5-c]pyridazinyl)methane- sulfonamide C 131

N-(1-(2,6- dimethoxyphenyl)-2-(5- methylfuran-2-yl)-1H-imidazo[4,5-b]pyrazin- 6- yl)methanesulfonamide B 132

N-(1-(2,6- dimethoxyphenyl)-2-(5- methylpyridin-3-yl)-1H-imidazo[4,5-b]pyrazin- 6- yl)methanesulfonamide C 133

N-(1-(2,6- dimethoxyphenyl)-2-(5- methylpyridin-3-yl)-1H-imidazo[4,5-b]pyrazin- 6- yl)cyclopropanesulfon- amide C 134

N-(1-(2,6- Dimethoxyphenyl)-2- propoxy-1H- imidazo[4,5-b]pyrazin- 6-yl)benzenesulfonamide C 135

N-(1-(2,6- Dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-5- hydroxy-1H-imidazo[4,5-b]pyrazin- 6- yl)methanesulfonamide B 136

N-(1-(2,6- Dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-5-(3-hydroxyazetidin-1- yl)-1H-imidazo[4,5- b]pyrazin-6-yl)methanesulfonamide C 137

N-(1-(2,6- Dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-5-vinyl-1H-imidazo[4,5- b]pyrazin-6- yl)methanesulfonamide B 138

N-(6-Chloro-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 5- yl)methanesulfonamide B 139

N-(7-(2,6- Dimethoxyphenyl)-8-(6- ethoxypyridin-2-yl)-6-methyl-7H-imidazo[4,5- c]pyridazinyl)methane- sulfonamide B 140

N-(1-(2,6- Dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-5-(hydroxymethyl)-1H- imidazo[4,5-b]pyrazin- 6- yl)methanesulfonamide B141

N-(5- ((Difluoromethoxy)methyl)- 1-(2,6- dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H- imidazo[4,5-b]pyrazin- 6- yl)methanesulfonamideB 142

N-(5-Chloro-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-1-(5- methylpyrimidin-2-yl)methanesulfonamide A 143

N-(5-Chloro-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6-yl)-1-(3- fluorophenyl)methane- sulfonamide B144

1-(5-chloropyrimidin-2- yl)-N-(7-(2,6- dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H- imidazo[4,5- c]pyridazinyl)methane- sulfonamideA 145

N-(5-Amino-1-(2,6- dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin- 6- yl)methanesulfonamide B 146

N-(1-(2,6- Dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-5-fluoro-1H-imidazo[4,5- b]pyrazin-6- yl)methanesulfonamide B

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, other embodiments are within the scope of the followingclaims

What is claimed is:
 1. A compound which is: 2

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142

or 143

2 N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6- yl)methanesulfonamide, 3N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1- phenylmethanesulfonamide, 41-cyclopropyl-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6- yl)methanesulfonamide, 5N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6- yl)benzenesulfonamide, 22N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6- yl)cyclopropanesulfonamide, 23N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)pyridine-2- sulfonamide, 24N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)pyridine-3- sulfonamide, 25N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)pyridine-4- sulfonamide, 26N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(pyridin-3-yl)methanesulfonamide, 27N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(pyridin-2-yl)methanesulfonamide, 28N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(pyrimidin-2-yl)methanesulfonamide, 292-cyclopropyl-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6- yl)ethanesulfonamide, 30N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)oxetane-3- sulfonamide, 31N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6- yl)cyclobutanesulfonamide, 32N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-N- methylmethanesulfonamide, 33cis-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-3-hydroxycyclobutane-1-sulfonamide, 34trans-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-3-hydroxycyclobutane-1-sulfonamide, 35N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(pyrimidin-5-yl)methanesulfonamide, 36N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)tetrahydro- 2H-pyran-4-sulfonamide,37 N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)morpholine- 4-sulfonamide, 38N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(piperidin-4-yl)methanesulfonamide, 39trans-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-4-hydroxycyclohexane-1-sulfonamide, 40cis-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-4-hydroxycyclohexane-1-sulfonamide, 41N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)pyrimidine- 2-sulfonamide, 42N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-4- hydroxypiperidine-1-sulfonamide,60 N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-3-hydroxy-3-methylbutane-1-sulfonamide, 61N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(1-hydroxycyclopropyl)methanesulfonamide, 64N-(5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6- yl)methanesulfonamide,69 N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(pyrazin-2-yl)methanesulfonamide, 70N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-2-hydroxy-2-methylpropane-1-sulfonamide, 71 (S)-N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(1-methyl-2-oxopiperidin-4- yl)methanesulfonamide, 72(R)-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(1-methyl-2-oxopiperidin-4- yl)methanesulfonamide, 73N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)pyrrolidine- 1-sulfonamide, 74N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)piperazine- 1-sulfonamide, 75N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)piperidine- 1-sulfonamide, 76N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-N′,N′- dimethylsulfamide, 77N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-N′-methyl- N′-cyclopropylsulfamide,78 N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(5-fluoropyridin-2-yl)methanesulfonamide, 79N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(5-fluoropyrimidin-2-yl)methanesulfonamide, 80N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(5-methylpyrimidin-2-yl)methanesulfonamide, 81trans-N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-((1r,3r)-3-hydroxy-3- methylcyclobutyl)methanesulfonamide, 82N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)but-2-yne-1- sulfonamide, 83N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(5-methylpyridin-2-yl)methanesulfonamide, 94N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(3-fluoropyridin-2-yl)methanesulfonamide, 95N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(pyridin-2-yl)methanesulfonamide, 96N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(5-fluoropyridin-2-yl)methanesulfonamide, 97N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)cyclopropanesulfonamide, 98 N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)morpholine-4-sulfonamide, 99N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-5-fluoropyridine-2-sulfonamide, 100N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6- yl)-1-(2-fluoro-4-methylphenyl)methanesulfonamide, 101N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-5-methylpyridine-2-sulfonamide, 102N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)pyridine-2-sulfonamide, 103 N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-4-(fluoromethyl)benzenesulfonamide, 104N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)pyridine-3-sulfonamide, 105 N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(5-fluoropyrimidin-2- yl)methanesulfonamide, 106N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-4-(difluoromethyl)benzenesulfonamide, 107N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6- yl)-1-(3-fluoro-4-methylphenyl)methanesulfonamide, 108N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(4-fluorophenyl)methanesulfonamide, 109N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(pyrimidin-2-yl)methanesulfonamide, 110N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)but-2-yne-1-sulfonamide, 111N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)tetrahydro-2H-pyran-4-sulfonamide, 112N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-N′-methyl-N′-cyclopropylsulfamide, 113N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6- yl)-1-(1-hydroxycyclopropyl)methanesulfonamide, 114N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(5-methylpyridin-2-yl)methanesulfonamide, 115N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-((1r,3r)-3-hydroxy-3- methylcyclobutyl)methanesulfonamide, 116N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-4-hydroxypiperidine-1-sulfonamide, 142N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(5-methylpyrimidin-2- yl)methanesulfonamide, or 143N-(5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(3-fluorophenyl)methanesulfonamide,

or a pharmaceutically acceptable salt thereof.
 2. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and one or more pharmaceutically acceptableexcipients.
 3. A compound which is:

or a pharmaceutically acceptable salt thereof.
 4. A compound which is:


5. A pharmaceutical composition comprising the compound of claim 3, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 6. A compound which is:

or a pharmaceutically acceptable salt thereof.
 7. A compound which is:


8. A pharmaceutical composition comprising the compound of claim 6, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 9. A compound which is:

or a pharmaceutically acceptable salt thereof.
 10. A compound which is:


11. A pharmaceutical composition comprising the compound of claim 9, ora pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 12. A compound which is:

or a pharmaceutically acceptable salt thereof.
 13. A compound which is:


14. A pharmaceutical composition comprising the compound of claim 12, ora pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 15. A compound which is:

or a pharmaceutically acceptable salt thereof.
 16. A compound which is:


17. A pharmaceutical composition comprising the compound of claim 15, ora pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 18. A compound which is:

or a pharmaceutically acceptable salt thereof.
 19. A compound which is:


20. A pharmaceutical composition comprising the compound of claim 19, ora pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.